Indications
Progesterone is available in various forms, each indicated for specific clinical uses. Gelatinized capsules are prescribed for the prevention of endometrial hyperplasia in non-hysterectomized, postmenopausal women who are undergoing treatment with conjugated estrogens tablets. These capsules are also used to manage secondary amenorrhea. Progesterone vaginal gel, in its 8% concentration, serves as a progesterone supplement or replacement during Assisted Reproductive Technology (ART) for women experiencing infertility due to progesterone deficiency, while the 4% concentration is intended for secondary amenorrhea. If the response to the 4% gel is inadequate, the 8% formulation is recommended. Vaginal inserts are designed to support embryo implantation and early pregnancy by enhancing corpus luteal function as part of ART for infertility. The intramuscular injection form is indicated for the treatment of amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology. Finally, progesterone in the form of tablets is used as a contraceptive to prevent pregnancy.
Pharmacodynamics
Progesterone exhibits a range of pharmacodynamic effects depending on its concentration, dosage form, and timing of administration. As the predominant hormone produced by the corpus luteum and placenta, progesterone facilitates the transition of the endometrium from the proliferative to the secretory phase, preparing the endometrium and corpus luteum for implantation. This hormone provides negative feedback to decrease follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, thereby preventing ovulation. In addition, it enhances endometrial vascularity and glandular development, accumulating glycogen and enlarging blood vessel surface areas. Progesterone also thickens cervical mucus post-ovulation, limiting sperm penetration. Within gelatinized capsules, progesterone mirrors endogenous effects, promoting secretory phase development and exerting antiestrogenic, anti-androgenic, and anti-aldosterone actions. Vaginal gel and inserts replicate natural progesterone effects, converting the endometrium to its secretory state to prepare for and maintain pregnancy. Intramuscular injection increases serum levels to counter unopposed estrogen-induced endometrial overgrowth, thus preventing abnormal bleeding. Lastly, contraceptive tablets inhibit ovulation, thicken cervical mucus, and alter endometrial conditions to prevent pregnancy.
Absorption
The absorption of progesterone depends on the route of administration. When orally administered as micronized soft-gelatin capsules, peak serum concentration is attained within three hours, though the bioavailability remains unquantified. In postmenopausal women, serum levels increase linearly with dosages between 100 mg/day and 300 mg/day. Intramuscular administration of progesterone in oil shows peak plasma concentrations at approximately 8 hours, with elevated plasma levels maintained for 24 hours. This route bypasses the hepatic first-pass effect, resulting in higher endometrial tissue concentrations compared to oral administration. Notably, vaginal administration achieves the highest endometrial concentrations. Progesterone-only contraceptive tablets reach peak serum progestin levels around two hours post-administration, with levels rapidly decreasing to baseline within 24 hours, necessitating strict adherence to dosing schedules.
Metabolism
Progesterone undergoes extensive hepatic metabolism, predominantly converting to metabolites such as 20α-hydroxy-Δ4-pregnenolone and 5α-dihydroprogesterone. Following oral administration, progesterone metabolites are excreted in bile and can be further metabolized within the gut through reduction, dehydroxylation, and epimerization processes. The primary plasma and urinary metabolites are consistent with those produced during physiological progesterone secretion from the corpus luteum.
Mechanism of Action
Progesterone engages with its nuclear receptor, known as the progesterone receptor (PR), which is a crucial component in the signaling mechanisms that maintain the endometrium in preparation for pregnancy. As part of the nuclear/steroid hormone receptor family, PR is a ligand-dependent transcription factor predominantly expressed in female reproductive tissues and the central nervous system. Upon interacting with progesterone, the PR modulates gene expression that governs the development, differentiation, and proliferation of target tissues. In humans, this receptor is notably expressed in stromal cells during both the secretory phase and pregnancy. Additionally, progesterone contributes to pregnancy prevention by altering cervical mucus consistency, making it less conducive to sperm penetration, and by suppressing follicle-stimulating hormone (FSH), which is essential for ovulation. When used perfectly, progestin-only oral contraceptives demonstrate a first-year failure rate of approximately 0.5%; however, typical use reflects a failure rate of about 5%, largely due to late or missed doses.
