Progesterone Micronized

Approved Indications

• Hormone Replacement Therapy (HRT):
  • Used with estrogen to prevent endometrial hyperplasia in postmenopausal women with an intact uterus.
• Secondary Amenorrhea:
  • Indicated for inducing withdrawal bleeding in women with amenorrhea due to hormonal imbalance (excluding anatomical causes).
• Assisted Reproductive Technology (ART):
  • Luteal phase support in women undergoing procedures such as IVF to enhance implantation and early pregnancy maintenance.
• Luteal Phase Deficiency:
  • For supplementing endogenous progesterone in natural or stimulated cycles.

Clinically Accepted Off-Label Uses

• Prevention of Preterm Birth:
  • Vaginal micronized progesterone is used in women with a short cervix or previous spontaneous preterm birth to reduce recurrence risk.
• Premenstrual Syndrome (PMS) / Premenstrual Dysphoric Disorder (PMDD):
  • Used in some women to manage mood, irritability, and physical symptoms.
• Menstrual Irregularities / Dysfunctional Uterine Bleeding:
  • Assists in regulating abnormal menstrual cycles.

Routes of Administration: Oral, Vaginal, Intramuscular (IM)

Adults

• HRT (Oral):
  • 200 mg at bedtime for 12 days per 28-day cycle (typically days 15–26).
  • Alternatively, 100 mg daily taken continuously with estrogen.
• Secondary Amenorrhea (Oral):
  • 400 mg once daily at bedtime for 10 days.
  • Withdrawal bleeding usually occurs within 7 days after the last dose.
• ART Luteal Support (Vaginal or IM):
  • Vaginal: 100–200 mg once or twice daily from embryo transfer until 10–12 weeks of pregnancy.
  • IM: 50–100 mg once daily from transfer until placental progesterone production is sufficient.
• Prevention of Preterm Birth (Off-label, Vaginal):
  • 100–200 mg once daily from 16–24 weeks of gestation until 36 weeks or delivery.

Elderly:

• Used only in postmenopausal women needing HRT.
• Prescribe lowest effective dose; assess cardiovascular and cancer risks prior to therapy.

Pediatric Use:

• Not indicated.

Renal/Hepatic Impairment:

• Hepatic: Contraindicated in severe liver disease due to extensive hepatic metabolism.
• Renal: Use with caution; monitor for signs of fluid retention.

Micronized progesterone is a natural form of the hormone progesterone. It binds to intracellular progesterone receptors in target tissues such as the uterus, breasts, and brain. In the endometrium, it converts the proliferative phase (stimulated by estrogen) into a secretory phase, making it suitable for implantation and pregnancy maintenance. It also regulates the hypothalamic-pituitary-gonadal axis by inhibiting gonadotropin-releasing hormone, reducing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Micronization improves oral absorption by reducing particle size, enhancing bioavailability.

• Absorption:
  • Oral: Rapid but limited due to first-pass hepatic metabolism; micronization improves absorption.
  • Vaginal: Absorbed directly into the uterus and bloodstream with higher local concentrations.
  • IM: Slow, sustained systemic release.
• Distribution:
  • Widely distributed; crosses placenta and blood-brain barrier.
  • Bound mainly to albumin and corticosteroid-binding globulin (>90%).
• Metabolism:
  • Primarily hepatic metabolism via CYP3A4 enzymes into inactive metabolites (e.g., pregnanediol).
• Excretion:
  • Mostly excreted in urine as glucuronide and sulfate conjugates.
• Bioavailability:
  • Oral: 10–15%
  • Vaginal: Higher local absorption
  • IM: Sustained systemic levels
• Half-life:
  • Oral: Approximately 13–18 hours
  • Vaginal: Variable
  • IM: Sustained levels for 24+ hours depending on dose

• Pregnancy:
  • FDA Category: B
  • Safe and commonly used in early pregnancy, particularly in ART and high-risk obstetrics.
  • No evidence of teratogenicity.
• Lactation:
  • Excreted in small quantities in breast milk.
  • Considered safe for breastfeeding; monitor infant for sedation or feeding issues with high maternal doses.

• Primary Class: Progestin Hormone
• Subclass: Natural (Bioidentical) Progestogen
• Formulation Note: Micronized for enhanced oral bioavailability

• Known hypersensitivity to progesterone or any ingredient in the formulation
• Undiagnosed abnormal vaginal bleeding
• Active or past thromboembolic disorders (e.g., DVT, PE, stroke)
• Active or history of hormone-dependent cancers (e.g., breast, endometrial)
• Severe hepatic impairment or active liver disease
• Missed abortion or incomplete miscarriage

• Thromboembolism Risk: Discontinue immediately if thrombosis is suspected.
• Depression or Mood Disorders: Use with caution; monitor psychological symptoms.
• Fluid Retention: May exacerbate conditions like renal, cardiac, or epileptic disorders.
• Visual Disturbances: Stop treatment if sudden visual loss or severe headaches occur.
• Cancer Risk: Use with estrogen may increase risk of breast and endometrial cancer—limit dose and duration.
• Monitoring Parameters:
  • Blood pressure
  • Liver function
  • Mammograms and pelvic exams for HRT users

Common:

• CNS: Drowsiness, dizziness, headache, fatigue
• GI: Nausea, abdominal pain, bloating
• Reproductive: Breast tenderness, spotting, menstrual irregularities
• General: Mood swings, fluid retention, weight gain

Serious/Rare:

• Thromboembolism (DVT, PE, stroke)
• Allergic reactions (rash, itching, urticaria)
• Depression or worsening psychiatric symptoms
• Migraine or visual changes

Dose-Related Notes:

• Sedation is more frequent with oral forms, especially at bedtime
• Vaginal and IM routes typically have fewer systemic effects

• CYP3A4 Inducers (e.g., rifampin, phenytoin, carbamazepine):
  • May reduce plasma levels and efficacy.
• CYP3A4 Inhibitors (e.g., ketoconazole, erythromycin):
  • May increase plasma concentrations and side effects.
• Estrogens:
  • Combined use increases risk of endometrial or breast cancer; careful risk-benefit evaluation required.
• Anticoagulants (e.g., warfarin):
  • May alter anticoagulant response—monitor INR closely.
• Alcohol:
  • Can enhance drowsiness and dizziness—avoid concurrent use.

• NICE Guidelines (2024):
  • Prefer micronized progesterone over synthetic progestins in HRT for lower risks of thromboembolism and breast cancer.
• WHO Recommendations (2023):
  • Vaginal progesterone supported for preterm birth prevention in high-risk pregnancies.
• ART Protocols (2024):
  • Continues to be first-line for luteal support in IVF and other ART cycles due to improved pregnancy outcomes.

• Temperature: Store below 25°C (77°F)
• Humidity: Store in a dry environment; protect from moisture
• Light: Protect from light; keep in original container
• Handling Instructions:
  • Oral: Take at bedtime with water
  • Vaginal: Use applicator; follow hygiene practices
  • IM: Administer by trained healthcare personnel
• Refrigeration: Not required unless stated by manufacturer
• Shelf Life: Usually 24–36 months; check manufacturer’s label