Micronized Progesterone

Mechanism

Mechanism of Action

Micronized progesterone is chemically identical to the endogenous luteal hormone secreted by the ovary. It acts by binding to the intracellular nuclear progesterone receptors (subtypes PR-A and PR-B) of the myometrial, stromal and decidual cells of the uterus.

Molecular Physiology of Quiescence Maintenance

1. Transcriptional regulation (Genomics): The progesterone-PR complex dimerizes and translocates to the nucleus, binding to progesterone response elements (PRE) of DNA. This selectively represses the expression of genes involved in uterine contractility, including oxytocin receptors (OXTR), connexin 43 (gap junction that synchronizes contractions), and inducible nitric oxide synthase isoenzymes.
2. Anti-inflammatory effect: It inhibits the migration of neutrophils, blocks the activation of the nuclear factor kappa B (NF-κB) cascade in the decidua and reduces the synthesis of proinflammatory interleukins (IL-1β, IL-6, IL-8), preventing the enzymatic degradation of cervical collagen.
3. Non-genomic pathway: It interacts with membrane receptors coupled to potassium channels and directly inhibits voltage-gated calcium channels, hyperpolarizing the uterine myocyte membrane.

Pharmacokinetics

Pharmacokinetics

• Routes of administration: Vaginal (route of choice for obstetric indications due to the direct local effect of the first uterine pass), oral (associated with a high rate of systemic adverse effects) and intramuscular (in the form of hydroxyprogesterone caproate, a sustained-release lipophilic preparation).
• Vaginal Route: It is absorbed directly through the vaginal mucosa. Micronization reduces the size of progesterone crystals, optimizing the rapid dissolving surface. It presents the "uterine first pass effect", achieving extremely high local myometrial and endometrial concentrations with minimal stable plasma levels, reducing liver toxicity.
• Oral Route: Very low bioavailability (< 10%) due to massive first-pass hepatic clearance. It undergoes enzymatic conversion by hepatic 5β-reductase to active metabolites of a sedative nature (such as pregnanolone and allopregnanolone).
• Half-life (t_1/2): Plasma about 5 to 10 hours after vaginal absorption through continuous tissue deposition.
• Excretion: Renal 95% in the form of inactive metabolites conjugated with glucuronic acid (pregnanediol glucuronide).

Indicators and dose

Indications

• Prevention of recurrent preterm birth in asymptomatic pregnant women with a history of spontaneous preterm birth.
• Reduction of preterm birth in pregnant women with a diagnosis of short cervix (cervical length 20-25 mm measured by transvaginal ultrasound between weeks 18 and 24).
• Luteal phase support as part of assisted reproductive technology (ART) protocols.
• Treatment of threatened spontaneous abortion in the first trimester (in women with a history of recurrent abortion).

Dosing and Precision Adjustment

• Prevention of preterm birth (Short neck or history): 200 µg in vaginal capsules once a day vaginally (introduced deeply into the posterior sac at night), started between weeks 16 and 20 of gestation and continued uninterruptedly until the completion of week 36.6 of gestation or until rupture of the membranes.
• Luteal phase support in ART: 400 to 800 mg per day vaginally divided into two doses, from the day of embryo transfer until completing week 10 to 12 of gestation.

Pregnancy and Breastfeeding

FDA Category A for validated ideal hormonal support. It does not present teratogenic effects nor does it associate fetal virilization at the indicated doses. Compatible with breastfeeding safely.

Security

Contraindications

• Known hypersensitivity to progesterone or peanut oil (used as an excipient in some commercial brands).
• Genital bleeding of undiagnosed etiology.
• Acute intermittent porphyria.
• History of active venous or arterial thromboembolism.
• Known or suspected hormone-sensitive neoplasia of the breast or genital tract.
• Severe liver dysfunction or failure.

Adverse Effects (ADR)

• Vaginal Route: Local irritation, vaginal pruritus, erythema of the mucosa and secretion of non-pathological viscous whitish residues.
• Oral Route (Systemic): Deep daytime sleepiness and dizziness (due to the binding of allopregnanolone to GABA-A receptors in the brain; therefore it is recommended to always take it at bedtime), transient headache, nausea and abdominal distension.
• Minor dermatological disorders: Mild gestational chloasma or melasma.

Interactions

Progesterone metabolism is accelerated by potent inducers of cytochrome CYP3A4 (rifampicin, phenytoin, carbamazepine), potentially compromising preventive tocolytic efficacy. Compatible and frequently combined with acute intermittent tocolysis with nifedipine or atosiban.