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Tuesday, July 29, 2025

Progesterone


Generic Name: Progesterone
Synonyms: P4, Natural Progesterone, Micronized Progesterone


Brand Names: Utrogestan, Prometrium, Crinone, Endometrin, Cyclogest, Prochieve, Gestone, Luteum, Progesta, YLena, among others


Drug Class: Progestins (Natural Progestogen)
Pharmaceutical Category: Female hormone; Endocrine-metabolic agent; Luteal support therapy
Route of Administration: Oral, vaginal, intramuscular (IM), transdermal (non-available in all markets), rectal

1. Pharmacological Classification

Progesterone is a naturally occurring steroid hormone and the principal endogenous progestogen in humans. It is a member of the C21 steroid family, derived from cholesterol, and it is essential for the maintenance of pregnancy and regulation of the menstrual cycle.

Unlike synthetic progestins (e.g., norethisterone, medroxyprogesterone acetate), natural progesterone has a lower incidence of metabolic and cardiovascular side effects, due to its compatibility with endogenous receptors.

2. Mechanism of Action

Progesterone acts by binding to intracellular progesterone receptors (PR-A and PR-B) located in target tissues such as the uterus, breast, brain, and hypothalamus. It works via two primary mechanisms:

  • Genomic pathway: Progesterone binds to its receptor, enters the nucleus, and modulates gene transcription. This alters protein synthesis related to endometrial transformation, pregnancy maintenance, and ovulation inhibition.

  • Non-genomic effects: Involves interaction with membrane-bound progesterone receptors, resulting in rapid signaling that affects ion channels and cellular excitability (notably in the nervous system).

3. Physiological Roles and Effects

  • Endometrium: Converts proliferative endometrium into secretory endometrium, preparing it for embryo implantation.

  • Ovaries: Maintains corpus luteum function during early pregnancy.

  • Central Nervous System: Modulates mood, sleep, and thermoregulation.

  • Breast: Involved in lobuloalveolar development.

  • Pregnancy: Prevents uterine contractions and supports placental function.

  • Hypothalamic-pituitary axis: Inhibits GnRH and LH surge, preventing ovulation when exogenously administered.

4. Clinical Indications

A. Gynecological and Reproductive Uses

  • Luteal phase support in Assisted Reproductive Technology (ART)

  • Amenorrhea (secondary) or irregular menstrual cycles

  • Endometrial protection in postmenopausal women receiving estrogen replacement therapy (ERT)

  • Prevention of preterm birth (particularly with history of spontaneous preterm delivery)

  • Infertility due to luteal phase defects

  • Menopausal hormone replacement therapy (HRT)

B. Obstetric Uses

  • Maintenance of early pregnancy (especially in patients with recurrent miscarriage or low progesterone levels)

  • Prevention of threatened abortion

C. Other Uses

  • Hormonal therapy in transgender women (as part of feminizing therapy)

  • Diagnosis of estrogen status (progesterone challenge test in amenorrhea)

5. Dosage and Administration

Oral Micronized Progesterone (Prometrium)

  • Menopausal HRT: 100 mg daily (continuous) or 200 mg at bedtime (12 days per 28-day cycle)

  • Amenorrhea: 400 mg daily for 10 days

  • Luteal phase support: 100–200 mg/day

Vaginal Progesterone (Crinone, Endometrin, Cyclogest)

  • Luteal support in ART: 90 mg gel daily or 100–400 mg capsule/suppository twice daily

  • Prevention of preterm birth: 200 mg vaginal capsule nightly

Intramuscular Injection (Gestone, Proluton)

  • 25–100 mg daily for luteal phase support or miscarriage prevention

  • IM route preferred in high-risk pregnancies but causes more pain and injection-site reactions

6. Pharmacokinetics

  • Absorption: Poor orally unless micronized; vaginal and IM routes offer better bioavailability.

  • Distribution: Lipophilic, distributed widely in body tissues, especially fat.

  • Metabolism: Extensive hepatic metabolism; major metabolites include pregnanediol and pregnanolone.

  • Elimination: Primarily via urine as glucuronide and sulfate conjugates.

7. Contraindications

  • Undiagnosed vaginal bleeding

  • Active or history of breast/genital malignancy (without specialist supervision)

  • Active or recent thrombophlebitis, thromboembolic disorders

  • Liver dysfunction or disease

  • Hypersensitivity to progesterone or formulation excipients

  • Incomplete abortion

8. Precautions and Monitoring

  • Thromboembolism: Assess history before use, especially in high-risk women.

  • Liver function: Monitor if used long-term or in liver disease history.

  • Depression history: Use cautiously in patients with mood disorders.

  • Visual changes or migraines: Discontinue if significant.

  • Glucose intolerance: May worsen glycemic control in diabetics.

  • Pregnancy: Widely used in pregnancy when indicated, particularly natural progesterone formulations.

9. Adverse Effects

Common

  • Fatigue, dizziness, drowsiness

  • Bloating, abdominal pain

  • Breast tenderness

  • Vaginal discharge (in vaginal use)

  • Mood swings or depression

  • Headache

Less Common

  • Nausea or vomiting

  • Edema

  • Acne or hirsutism (less common than with synthetic progestins)

  • Spotting or irregular bleeding

  • Weight gain or appetite changes

Rare but Serious

  • Thromboembolic events: DVT, pulmonary embolism

  • Anaphylactic reactions (IM formulations with castor oil)

  • Liver dysfunction (rare with natural progesterone)

  • Severe depression or suicidal ideation

10. Drug Interactions

Cytochrome P450 inducers

  • Rifampin, carbamazepine, phenytoin: Decrease progesterone effectiveness due to increased metabolism.

Anticoagulants

  • May alter coagulation profile; monitor INR in patients on warfarin.

Estrogens

  • Co-administration (e.g., in HRT) increases risk of breast cancer and thromboembolic events when used long-term.

CYP inhibitors

  • Ketoconazole or erythromycin may increase plasma levels and side effects of progesterone.

Other sedatives

  • Combined sedative effects with benzodiazepines, alcohol, opioids, especially when taking oral progesterone.

11. Use in Special Populations

Pregnancy (Category B)

  • Safe and widely used in pregnancy maintenance.

  • Vaginal and IM progesterone particularly used in ART and recurrent miscarriage.

Lactation

  • Safe. Progesterone appears in low amounts in breast milk; no adverse infant effects reported.

Elderly

  • Limited indications; primarily used for HRT in postmenopausal women.

Pediatrics

  • Not typically used; safety and efficacy not well studied in children.

12. Formulations and Products

  • Micronized Progesterone Capsules: Prometrium (100 mg, 200 mg)

  • Vaginal Gel: Crinone (4% or 8%)

  • Vaginal Capsules: Utrogestan, Cyclogest (100–400 mg)

  • Suppositories: Endometrin (100 mg)

  • Injectable Solutions: Gestone (25–100 mg/mL), Proluton (hydroxyprogesterone caproate—long-acting)

  • Creams: Over-the-counter topical progesterone creams exist but vary widely in quality and systemic absorption

13. Clinical Notes and Comparisons

  • Micronized natural progesterone is superior to synthetic progestins in terms of lipid profile impact, clotting risk, and mood side effect profile.

  • Synthetic progestins (e.g., medroxyprogesterone acetate) may have more potent progestogenic effects but are associated with higher risk of breast cancer, thromboembolic events, and unfavorable metabolic changes.

  • Vaginal progesterone delivers high local uterine concentrations with fewer systemic side effects and is first-line in luteal phase support.

  • IM progesterone provides reliable serum levels but is painful and associated with injection site complications.




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