What is the mechanism of action of progestins?

Mechanism of Action of Progestins

Progestins work through multiple mechanisms including suppression of ovulation, thickening of cervical mucus, transformation of proliferative endometrium into secretory endometrium, and alteration of the endometrium to prevent implantation.

Primary Mechanisms

Progestins exert their effects primarily through binding to progesterone receptors (PR-A and PR-B), which are found throughout the reproductive system. The main mechanisms include:

Reproductive System Effects

• Endometrial transformation: Progestins transform proliferative endometrium into secretory endometrium 1
• Cervical mucus thickening: Inhibits sperm penetration 2
• Ovulation suppression: Inhibits pituitary gonadotropin secretion (LH and FSH), preventing follicular maturation and ovulation 2, 1
• Fallopian tube effects: Slows the movement of the ovum through the fallopian tubes 2
• Endometrial changes: Alters the endometrium to prevent implantation 2

Anti-inflammatory and Other Effects

• Anti-inflammatory action: Counteracts inflammatory processes 3
• Local progesterone increase: Increases progesterone in gestational tissues to counteract functional decreases 3
• Prostaglandin synthesis reduction: Decreases prostaglandin synthesis 3
• Cytokine production modulation: Reduces infection-mediated cytokine production 3

Molecular Mechanisms

At the molecular level, progestins work through several pathways:

• Progesterone receptor modulation: Changes in PR-A and PR-B expression (decreased PR-A/PR-B ratio maintains uterine quiescence) 3
• Gene regulation: When stimulated by progestins, PRs help promote selected genes or prevent binding of other factors 3
• Cortisol regulation: Interfere with cortisol-mediated regulation of placental gene expression 3
• Non-genomic pathways: Act through mechanisms independent of gene transcription 3

Tissue-Specific Effects

Progestins have different effects on various tissues:

Cervix

• Reduce cervical stromal degradation 3
• Alter barrier to ascending inflammation/infection 3

Myometrium

• Reduce contraction frequency 3
• Bind to membrane-bound PRs 3

Decidua

• Attenuate response to hemorrhage/inflammation 3

Fetal Membranes/Placenta

• Alter estrogen synthesis 3
• Alter fetal endocrine-mediated effects 3

Pharmacological Classification

Progestins are classified based on their structure:

1. Natural progesterone: The physiological hormone 4
2. Progesterone derivatives: Including medrogestone 4
3. 17α-hydroxyprogesterone derivatives: Including medroxyprogesterone acetate, cyproterone acetate 4
4. 19-norprogesterone derivatives: Including nomegestrol, promegestone 4
5. 19-nortestosterone derivatives: Including norethisterone, levonorgestrel 4
6. Spironolactone derivatives: Including drospirenone 4

Clinical Applications

The mechanism of action of progestins makes them useful for:

• Contraception: Through multiple mechanisms including ovulation suppression 2
• Endometrial protection: Prevention of endometrial hyperplasia during estrogen therapy 5
• Menstrual regulation: Treatment of dysfunctional uterine bleeding 5
• Preterm birth prevention: In high-risk pregnancies 5

Important Considerations

• Some synthetic progestins are prodrugs that need to be metabolized to become active 4
• Different progestins have varying affinities for other steroid receptors (androgenic, estrogenic, glucocorticoid) 6
• Newer progestins (fourth generation) have been designed to minimize side effects related to androgenic, estrogenic, or glucocorticoid receptor interactions 7
• The potency and side effect profile varies significantly between different progestins 8

Understanding these mechanisms helps explain both the therapeutic benefits and potential side effects of progestin therapy in various clinical contexts.