Progesterone receptor modulators

Progesterone receptor modulators (PRMs) represent a pharmacological class of synthetic agents that interact with progesterone receptors (PRs) and exert variable effects depending on the tissue context—acting as agonists, antagonists, or partial agonists. This tissue-selective behavior distinguishes PRMs from traditional progestins and provides therapeutic advantages in various gynecological, obstetric, and oncological conditions. They are structurally designed to bind with high affinity to progesterone receptors A and B, modulating gene expression in target cells.

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1. Classification of Progesterone Receptor Modulators

Progesterone receptor modulators can be classified based on their predominant action and clinical purpose into three major categories:

A. Selective Progesterone Receptor Modulators (SPRMs)

• Act as agonists in some tissues and antagonists in others

• Exhibit tissue-selective modulation of PR signaling

• Examples: ulipristal acetate, mifepristone (in low doses), vilaprisan

B. Progesterone Receptor Antagonists

• Purely block PR activity

• Prevents all progesterone-mediated signaling

• Example: mifepristone (in high doses)

C. Mixed/Partial Agonists-Antagonists

• Function varies with receptor isoform, tissue type, and endogenous progesterone level

• May modulate the endometrium differently from classical progestins

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2. Mechanism of Action

Progesterone receptor modulators bind competitively to nuclear progesterone receptors (PR-A and PR-B), preventing endogenous progesterone from exerting its effects. Based on their structure and the cellular co-regulators present, they may:

• Antagonize PRs in the endometrium or pituitary gland (suppressing ovulation)

• Agonize PRs in other tissues (e.g., cervix, hypothalamus)

• Alter gene transcription and modulate hormonal feedback loops

Some key actions include:

• Inhibiting ovulation by blocking the LH surge

• Inducing endometrial atrophy and apoptosis of leiomyoma cells

• Promoting cervical softening and uterine contractions at higher doses (used in abortion)

• Altering glycodelin and other endometrial proteins, affecting implantation

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3. Therapeutic Applications

A. Emergency Contraception

• Ulipristal acetate (UPA) 30 mg single oral dose

• Effective within 120 hours (5 days) post-unprotected intercourse

• Delays ovulation by inhibiting the LH surge

B. Medical Termination of Pregnancy

• Mifepristone (RU-486) used with misoprostol

• Blocks progesterone’s support of early pregnancy

• Induces decidual breakdown and cervical ripening

C. Uterine Fibroids (Leiomyomas)

• Ulipristal acetate 5 mg daily for up to 3 months

• Reduces fibroid volume and associated bleeding

• Promotes amenorrhea through endometrial suppression

D. Cushing’s Syndrome

• Mifepristone (Korlym) approved for glucocorticoid receptor antagonism

• Improves hyperglycemia in patients with Cushing’s-related type 2 diabetes

E. Endometriosis (Investigational)

• SPRMs like vilaprisan and telapristone acetate are in trials for symptom control

F. Progesterone-Sensitive Cancers (Investigational and limited use)

• Potential applications in hormone-responsive cancers (e.g., breast, endometrial) via antiprogesterone effects

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4. Pharmacokinetics and Metabolism

Ulipristal acetate

• Absorption: Well absorbed orally, peak plasma levels in 1–2 hours

• Half-life: ~32 hours

• Metabolism: Hepatic via CYP3A4

• Excretion: Feces and urine

Mifepristone

• Absorption: Oral bioavailability > 60%

• Half-life: 20–90 hours (high protein binding prolongs activity)

• Metabolism: Hepatic, primarily by CYP3A4

• Excretion: Feces

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5. Generic Drug Names and Brand Examples

Generic Name	Brand Name(s)	Indications
Mifepristone	Mifeprex, Korlym	Medical abortion, Cushing’s syndrome
Ulipristal acetate	Ella, Esmya	Emergency contraception, uterine fibroids
Vilaprisan (investigational)	–	Uterine fibroids, endometriosis (clinical trials)
Asoprisnil (investigational)	–	Uterine fibroids (discontinued in development)
Telapristone acetate (CDB-4124)	–	Cancers, fibroids (under research)

6. Adverse Effects

Ulipristal acetate

• Headache

• Nausea

• Abdominal pain

• Menstrual delay or spotting

• Breast tenderness

• Dizziness

• Fatigue

Mifepristone

• Vaginal bleeding (heavy, prolonged in some cases)

• Abdominal cramping

• Gastrointestinal upset

• Infection risk if fetal tissue remains post abortion

• Adrenal insufficiency (at high doses for Cushing's)

Long-term use concerns (particularly for fibroids):

• Endometrial changes (PAEC: Progesterone Receptor Modulator-Associated Endometrial Changes), which are non-neoplastic but require monitoring

• Liver injury (rare but significant with UPA – some restrictions in Europe following liver failure reports)

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7. Contraindications

• Confirmed or suspected pregnancy (except for abortion use)

• Unexplained vaginal bleeding

• Liver impairment or hepatic disease (especially with UPA for fibroids)

• Adrenal failure (mifepristone affects cortisol binding)

• Concurrent use with potent CYP3A4 inducers (e.g., rifampicin) or inhibitors (e.g., ketoconazole)

• Porphyria

• Allergy to drug components

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8. Precautions

• Endometrial monitoring: Necessary if used long-term for fibroids due to reversible endometrial thickening

• Pregnancy status: Rule out before initiating treatment

• Contraception: Hormonal contraception may be impaired due to PRM action; recommend non-hormonal methods during and shortly after use

• Liver function monitoring: Required during treatment for fibroids

• Infection risk: After mifepristone + misoprostol abortion, rare fatal sepsis has occurred; prompt medical attention is required for fever/pain

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9. Drug Interactions

CYP3A4 interactions:

• Inducers (e.g., rifampicin, carbamazepine) may reduce PRM efficacy

• Inhibitors (e.g., ketoconazole, itraconazole) may increase drug exposure and toxicity

Hormonal contraceptives:

• May be less effective during or immediately after PRM use

• PRMs themselves interfere with progesterone receptor binding, making hormonal methods unreliable

Anticoagulants:

• Use caution as PRMs like mifepristone may cause heavy bleeding

Glucocorticoids:

• Mifepristone may antagonize corticosteroid action, complicating treatment in individuals requiring glucocorticoids

Warfarin and NSAIDs:

• May potentiate bleeding risks when used with mifepristone

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10. Clinical Considerations and Monitoring

Emergency contraception (Ulipristal acetate):

• Take as early as possible within 120 hours of unprotected intercourse

• Delay hormonal contraceptive restart for at least 5 days after UPA

Medical abortion (Mifepristone):

• Used with misoprostol (typically 200 mg mifepristone followed by 800 mcg misoprostol)

• Requires follow-up for confirmation of complete abortion

• Counsel patients regarding expected bleeding, pain, and need for emergency care if severe symptoms occur

Uterine fibroids (UPA):

• Limited to short-term intermittent use (e.g., 3-month cycles)

• Monitor LFTs before, during, and after treatment

• Regular ultrasound to assess fibroid size and endometrial changes

Cushing’s syndrome (Mifepristone/Korlym):

• Monitor glucose and cortisol-related symptoms

• Not suitable for pregnancy or women trying to conceive

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11. Regulatory and Safety Notes

• EMA (European Medicines Agency) restricted ulipristal acetate for fibroids due to rare but serious liver injury reports. Emergency contraception use is still allowed with warnings.

• FDA-approved uses:

  • Mifepristone: for termination of intrauterine pregnancy up to 70 days (Mifeprex); and for hyperglycemia in Cushing’s syndrome (Korlym)

  • Ulipristal acetate: emergency contraception (Ella)

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12. Summary of Key Generic PRMs

• Mifepristone

• Ulipristal acetate

• Vilaprisan (under clinical investigation)

• Telapristone acetate (investigational)

• Asoprisnil (development discontinued)