Gestagens (Progestogens)

Physiology and Mechanism of Action

Natural progesterone is synthesized in the ovaries (by the corpus luteum during the luteal phase), placenta, testes, and partially in the adrenal cortex. Its production is stimulated by luteinizing hormone (LH), the secretion of which progesterone suppresses via negative feedback.

The hormone crosses the plasma membrane and binds to a cytosolic receptor. This causes chaperone proteins to dissociate from the receptor, which is then phosphorylated and forms dimers. The complex enters the nucleus, binds to DNA, and initiates transcription of specific target genes.

Key physiological effects:

• Reproductive system: Induces secretory transformation of the endometrium (preparing for implantation), thickens cervical mucus (creating a barrier to sperm), reduces myometrial tone (tocolytic effect), and stimulates the growth of mammary gland glandular tissue.
• Metabolism: Increases hepatic glycogen stores, stimulates insulin release, increases lipoprotein lipase activity (fat storage), and reduces sodium reabsorption by competing with aldosterone.

Classification of Synthetic Gestagens

Synthetic agents are divided into three groups. Their critical feature is the ability to bind to 'off-target' receptors (androgen, estrogen, mineralocorticoid), which determines each drug's individual profile.

1. Progesterone derivatives. Addition of a methyl group at the $C_6$ position increases oral bioavailability and activity.
2. Examples: medroxyprogesterone, megestrol, dydrogesterone, cyproterone.
3. Feature: cyproterone exhibits pronounced antiandrogenic activity.

1. 19-Nortestosterone derivatives. Characterized by the replacement of the methyl group at the $C_{19}$ position with hydrogen. This group is heterogeneous in its effects.
2. With an ethynyl radical: estrane derivatives (norethisterone — has estrogenic and androgenic effects) and gonane derivatives (levonorgestrel — retains residual androgenic activity).
3. Without an ethynyl radical: dienogest (notable for its antiandrogenic activity).

1. Spironolactone derivatives.
2. Example: drospirenone.
3. Feature: profile is as close to natural progesterone as possible. Possesses potent antimineralocorticoid activity (prevents sodium and water retention).

Clinical Application

Gestagens are used as monotherapy or in combination (most frequently with ethinylestradiol):

• Contraception: As a component of combined oral contraceptives (COCs). Levonorgestrel is used for emergency contraception (taken as a 0.75 mg dose twice, 12 hours apart, within 48–72 hours after unprotected intercourse).
• Hormone replacement therapy (HRT): Added to estrogens to protect the endometrium from hyperplasia and carcinoma. In this context, a pronounced antiestrogenic effect of the gestagen is undesirable as it can negate the cardiovascular and bone-protective benefits of estrogens.
• Treatment of hyperandrogenism: COCs containing antiandrogenic gestagens (cyproterone, dienogest, drospirenone) are used for acne, hirsutism, and alopecia.
• Gynecological pathology: Dydrogesterone is used for endocrine-related recurrent miscarriage. Levonorgestrel-releasing intrauterine systems are effective for endometriosis and uterine fibroids.

Antigestagens

This is a group of substances that block the action of progesterone by competing for its receptors. The primary representative is mifepristone (a 19-norethisterone derivative).

Indications for use (strictly under medical supervision):

1. Medical termination of pregnancy in the first trimester (single dose, followed 48 hours later by prostaglandins to induce expulsion of the conceptus).
2. Labor induction (for cervical ripening and dilation at term gestation).
3. Emergency contraception (via ovulation suppression).