Home Supplements That Start With E Ethisterone Explained: Progestin Therapy, Health Effects, and Modern Alternatives

Ethisterone Explained: Progestin Therapy, Health Effects, and Modern Alternatives

10

Ethisterone is a first-generation, orally active progestin developed in the mid-20th century. As a synthetic agonist of the progesterone receptor, it can stabilize the endometrium, reduce bleeding, and oppose unopposed estrogen in the uterus. Historically, it was tried for recurrent miscarriage and abnormal uterine bleeding, sometimes combined with diethylstilbestrol (DES). Over time, newer progestins and micronized progesterone largely replaced ethisterone, owing to better selectivity, more predictable pharmacokinetics, and fewer androgen-like effects. Today, ethisterone is rarely used in routine practice; if you encounter it, it will usually be in older studies, historical protocols, or legacy formularies. This guide translates the evidence into plain language: what ethisterone is, where it was used, typical historical dosing, who should avoid it, and how modern options compare so you can understand when a progestin truly fits—and when it does not.

Key Insights on Ethisterone

  • First oral progestin; stabilizes the endometrium but is largely superseded by newer agents.
  • Historical pregnancy trials (often with DES) did not show clear benefit and raised safety concerns for exposed mothers and offspring.
  • Historical regimens ranged roughly from 25–250 mg/day in late pregnancy protocols; not a modern first-line dose or indication.
  • Avoid in pregnancy, in people with hormone-sensitive cancers or significant liver disease; consider modern, guideline-supported alternatives instead.

Table of Contents

What is ethisterone and how does it work?

Ethisterone (17α-ethynyltestosterone) is an early oral progestin—the first to be taken by mouth—designed to mimic progesterone’s “progestational” effects. Progestational activity means it binds and activates the progesterone receptor (PR) in endometrial tissue, transforming the uterine lining from proliferative to secretory. That transformation stabilizes the endometrium, decreases unplanned shedding, and counterbalances estrogen’s growth-promoting effects. Clinically, those actions can reduce heavy or irregular bleeding and provide endometrial protection when estrogen is used for other reasons.

Chemically, ethisterone belongs to the testosterone-derived (estrane) family of progestins. Members of this family often retain some androgen receptor activity. That “androgenicity”—manifesting as oilier skin, acne, hirsutism, lipid changes, or mood shifts in some users—was one reason clinicians moved toward newer, more selective progestins or to micronized progesterone. Many later agents were engineered to preserve endometrial actions while minimizing activity at non-target receptors (androgen, mineralocorticoid, glucocorticoid).

Compared with micronized progesterone, ethisterone’s oral bioavailability and receptor profile are different. Micronized progesterone exerts progestational effects with minimal androgenicity but is subject to first-pass metabolism and may cause sedation at higher doses. By contrast, ethisterone’s androgenic profile can be clinically apparent at therapeutic doses, especially at the higher dose ranges used historically. Because modern care favors efficacy with a cleaner side-effect profile, ethisterone has faded from frontline use—yet understanding it helps explain how progestin design evolved and why specific molecules are preferred for specific jobs today.

Back to top ↑

Where was ethisterone used and does it work?

Historically, ethisterone was prescribed for abnormal uterine bleeding (AUB), luteal-phase support, and prevention of miscarriage. In the mid-20th century, investigators also combined high-dose estrogen (most often diethylstilbestrol, DES) with ethisterone in attempts to reduce fetal loss in high-risk pregnancies (for example, in diabetic mothers). Those strategies did not become standard care, and subsequent long-term follow-ups raised safety concerns.

For miscarriage prevention, modern evidence distinguishes between: (1) threatened miscarriage (bleeding with a viable intrauterine pregnancy) and (2) recurrent miscarriage (two or three or more prior losses, depending on definition). Across these contexts, ethisterone itself is not recommended today. Trials that included ethisterone (usually in combination with DES) failed to demonstrate net clinical benefit and were later associated with adverse maternal and offspring outcomes in long-term follow-up cohorts. Contemporary randomized evidence and guidelines—focused on progesterone, not ethisterone—are far more selective. Vaginal micronized progesterone may help certain women with bleeding in early pregnancy who also have a prior miscarriage history, whereas routine use in all comers with bleeding shows little or no benefit. In recurrent miscarriage without bleeding, results are mixed; some modern trials show no improvement with first-trimester progesterone alone, and recommendations vary by guideline.

For AUB and endometrial protection outside of pregnancy, modern practice favors better-characterized options: norethindrone (norethisterone), norethindrone acetate, levonorgestrel intrauterine systems, drospirenone-only pills, and cyclic or continuous micronized progesterone in menopausal hormone therapy. These choices are supported by contemporary pharmacology and outcomes data, and they generally carry more predictable side-effect profiles than ethisterone.

Bottom line: ethisterone’s historical roles have been replaced by agents with clearer benefits and less androgenicity. When a progestin is warranted, clinicians choose the molecule and route that match the indication (e.g., vaginal micronized progesterone for specific early-pregnancy scenarios; levonorgestrel IUS for heavy bleeding; oral norethindrone for scheduled endometrial exposure), rather than reaching for ethisterone.

Back to top ↑

How was ethisterone dosed historically?

Ethisterone dosing varied widely across legacy protocols and often accompanied high-dose estrogens. Typical modern-style dosing tables do not exist because the drug has largely fallen out of use. However, several well-documented historical regimens illustrate the range:

  • Pregnancy protocols with DES: In randomized work on high-risk diabetic pregnancies, women received escalating DES plus ethisterone during the second half of gestation. Ethisterone dosing began as low as 25 mg/day and increased to 250 mg/day by around 32 weeks, continuing to term in some protocols. Those trials did not yield durable clinical benefits, and long-term follow-ups reported maternal and offspring harms.
  • Cyclic gynecologic use (mid-century): Early reports used oral courses during cycle days 5–25 at doses from 5–50 mg/day, aiming to convert or stabilize the endometrium. These reports pre-dated today’s evidence hierarchy and were later overshadowed by safer or more effective regimens using other progestins.
  • Context matters: Dose targets depended on the clinical intent—endometrial stabilization vs late-pregnancy “support”—and on co-administration with estrogens. Because ethisterone carried more androgenic activity than modern options, higher doses increased the likelihood of acne, hirsutism, and lipid changes.

Crucial note: These doses are historical and not modern standards of care. If a clinician today seeks luteal or endometrial support, they choose more selective agents (e.g., micronized progesterone, dydrogesterone where available, norethindrone, levonorgestrel IUS) and tailor doses to indication, route, and guideline.

If you encounter an old study or a legacy prescription referencing ethisterone, treat its dose/duration as an archival artifact, not a current template. For present-day decision-making, rely on updated guidelines and progestin-specific evidence.

Back to top ↑

Side effects and risks to watch for

Because ethisterone is testosterone-derived, it can activate androgen receptors alongside progesterone receptors. That off-target activity explains several side effects:

  • Androgenic effects: acne, seborrhea, increased facial or body hair growth (hirsutism), and—less commonly—scalp hair thinning in susceptible individuals.
  • Metabolic and lipid changes: potential shifts toward less favorable lipid profiles with higher or prolonged dosing; newer agents often mitigate this risk.
  • Mood and neurologic effects: irritability, low mood, or headaches can occur with any progestin; susceptibility varies.
  • Breast and gynecologic symptoms: mastalgia, breakthrough bleeding or spotting, and cycle irregularity during initiation or dose moves.
  • Hepatic considerations: all sex-steroid hormones are hepatically metabolized; avoid in active liver disease or significant hepatic impairment.
  • Pregnancy exposure: historical high-dose DES+ethisterone exposures in utero were not benign. Long-term follow-ups reported more urogenital anomalies in exposed children and possible male sexual function effects; exposed mothers had more tumors of the reproductive tract (mostly benign) and more breast cancers reported in the hormone-exposed group in one follow-up analysis.

As with any progestin, rare idiosyncratic reactions can occur. But in modern practice the key risk conversation is comparative: ethisterone’s androgenicity and historical safety concerns make it a poor choice when multiple better-tolerated, well-studied alternatives exist.

If a patient reports androgenic symptoms on an older or nonselective progestin, clinicians often switch to a less androgenic option (e.g., micronized progesterone, dydrogesterone, or drospirenone-containing regimens where appropriate), or change route of delivery (e.g., vaginal progesterone or levonorgestrel IUS).

Back to top ↑

Who should avoid it and safer modern options

Given its profile and the availability of better options, most people should avoid ethisterone. Specific groups where avoidance (or, at minimum, strong caution) is appropriate include:

  • Pregnancy: Do not initiate ethisterone. Historical pregnancy regimens combining DES+ethisterone lacked clear benefit and raised safety concerns for both mother and child. Where progestogen is considered today, guidelines specify vaginal micronized progesterone for narrow populations with bleeding and a prior miscarriage, with defined doses and time limits.
  • Hormone-sensitive cancers: Avoid in current or prior breast cancer, or endometrial cancer, unless a specialist explicitly recommends and supervises therapy.
  • Active liver disease: Avoid in cholestasis, active hepatitis, or significant hepatic dysfunction.
  • Unexplained vaginal bleeding: Evaluate first; do not mask a diagnosis with empiric hormones.
  • High cardiovascular risk without clear indication: Prefer alternatives with better lipid or blood-pressure neutrality.

Safer modern alternatives by goal:

  • Preventing early miscarriage in select cases: Vaginal micronized progesterone 400 mg twice daily until 16 completed weeks only when criteria are met (viable intrauterine pregnancy on scan, early bleeding, and at least one prior miscarriage), per updated guideline statements. Routine use without these features is not supported.
  • Heavy or irregular bleeding (AUB): Levonorgestrel intrauterine system (local endometrial exposure), norethindrone / norethindrone acetate in structured courses, or combined hormonal contraception if not contraindicated.
  • Endometrial protection with estrogen therapy: Cyclic or continuous micronized progesterone or a levonorgestrel IUS.
  • Endometriosis or pelvic pain: Progestin-based regimens (e.g., dienogest where available), levonorgestrel IUS, or GnRH analogs per guideline pathways.

These choices reflect contemporary pharmacology and outcome data, emphasizing the right molecule, route, and duration for the job—without the unintended androgenic baggage typical of older agents like ethisterone.

Back to top ↑

What the evidence says today

Reading the ethisterone story through a modern lens explains why it is no longer standard:

  1. Historical pregnancy strategies fell short. Randomized work initiated in 1950 tested high-dose DES plus ethisterone in diabetic pregnancies. Decades-later follow-ups found no lasting benefit on the original intent and safety signals: in the hormone-exposed mothers, more tumors of the reproductive tract (mostly benign) and more breast cancers were reported, while among exposed children, urogenital anomalies were more frequent and male sexual function markers were less favorable. Those outcomes, together with evidence that DES alone lacked therapeutic value in pregnancy, ended enthusiasm for such regimens.
  2. Progesterone in early pregnancy is selective, not universal. Large, modern randomized trials and systematic reviews show that routine first-trimester progesterone does not improve live birth for all women with early bleeding or all with recurrent miscarriage. Subgroup signals suggest benefit for specific women (e.g., bleeding plus a prior miscarriage), which is reflected in contemporary guideline updates specifying vaginal micronized progesterone 400 mg twice daily with strict eligibility and a stop at 16 completed weeks if a fetal heartbeat is confirmed. None of these modern recommendations involve ethisterone.
  3. Pharmacology favors newer progestins. Structure–activity research across progestins shows trade-offs among PR potency and androgen, mineralocorticoid, or glucocorticoid activity. Ethisterone, as an early testosterone-derived progestin, sits on the less selective end of that spectrum. Fourth-generation agents and micronized progesterone were developed specifically to improve selectivity and tolerability.

Practical takeaway: If you are scanning old protocols that include ethisterone, treat them as historical. For current care, match the indication to a modern, guideline-backed agent and dose. Reserve progesterone in early pregnancy for the scenarios where it helps; pick local (intrauterine) or selective systemic options for bleeding and endometrial protection; and avoid ethisterone’s androgenic liabilities.

Back to top ↑

References

Disclaimer

This article is for general information only and does not replace personalized medical advice, diagnosis, or treatment. Do not start, stop, or change any medication (including hormones) without discussing your specific situation, risks, and goals with a qualified healthcare professional.

If you found this guide useful, consider sharing it on Facebook, X (formerly Twitter), or your favorite platform, and follow us for future updates. Your support helps us continue producing careful, high-quality health content.

facebookShare on Facebook
TwitterPost on X
FollowFollow us

RELATED ARTICLESMORE FROM AUTHOR