Combined Oral Contraceptives (COCs)

Mechanism

Mechanism of Action

Combined oral contraceptives act by suppressing the hypothalamic-pituitary-ovarian axis through central negative feedback.

Physiology of Pharmacological Anovulation

1. Gonadotropin Inhibition:
- The estrogenic component (typically Ethinylestradiol or estradiol valerate) selectively suppresses the secretion of follicle-stimulating hormone (FSH) by the adenohypophysis, blocking follicular recruitment and maturation of the dominant ovarian follicle.
- The progestogen component (levonorgestrel, desogestrel, gesturedene or drospirenone) inhibits the pulsatile secretion of luteinizing hormone (LH) by the hypothalamus and pituitary gland, completely preventing the acute LH surge that triggers ovulation.
2. Secondary peripheral effects: Alteration of cervical mucus (it becomes dense, cellular, scarce and impermeable to the penetration of sperm), endometrial decidual atrophy that prevents the implantation of a blastocyst, and reduction of motility and ciliary secretion in the fallopian tubes.

Components and Classification of Progestogens

While the usual estrogen is ethinyl estradiol (doses varying from 15 to 35 µg), the progestogen determines the metabolic and tolerability profile:

• Second Generation (Levonorgestrel): Excellent cardiovascular safety profile, lower risk of relative venous thromboembolism, but exhibits moderate residual androgenic activity (may worsen acne or hirsutism).
• Third Generation (Desogestrel, Gestodene): Greater progestational selectivity, androgenic effects decrease, but are associated with a relative increase in the risk of venous thromboembolism.
• Fourth Generation / Antiandrogenics (Drospirenone, Cyproterone Acetate): Drospirenone is a derivative of spironolactone with antimineralocorticoid and direct antiandrogenic properties (decreases water retention and acne). Cyproterone acetate is an androgen receptor antagonist indicated for severe hirsutism.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid and almost complete orally. Ethinyl estradiol undergoes sulfation in the intestinal wall and first-pass hepatic oxidative metabolism, achieving a net bioavailability of 45-60%.
• Metabolism: Hepatic through hydroxylation catalyzed by the CYP3A4 system, followed by conjugation with glucuronide and sulfate. It undergoes enterohepatic circulation (intestinal bacterial conjugates hydrolyze them allowing their reabsorption).
• Half-life (t_1/2): Ethinylestradiol approx. 12 to 24 hours; progestins vary from 12 hours (levonorgestrel) to 30 hours (drospirenone).
• Excretion: Mixed urinary and biliary-fecal route.

Indicators and dose

Indications

• Highly effective reversible hormonal contraception (Pearl index < 0.1 with ideal use).
• Treatment of moderate to severe acne vulgaris and manifestations of hirsutism (especially preparations with drospirenone or cyproterone).
• Treatment of primary dysmenorrhea and pelvic pain associated with endometriosis.
• Treatment of abnormal uterine bleeding due to dysfunctional causes or fibroids.
• Regulation of the menstrual cycle in Polycystic Ovary Syndrome (PCOS).

Dosage and Administration

Usual regimens of daily administration at the same time for a period of 21 consecutive days followed by a rest or placebo interval of 7 days (21/7 schedule), or 24 days of active hormone with 4 days of placebo (24/4 schedule, reduces the risk of follicular escape development and mitigates symptoms due to estrogen deprivation).

Pregnancy and Breastfeeding

Contraindicated in pregnancy. If pregnancy occurs, intake should be stopped immediately; Epidemiological studies do not show teratogenicity at accidental low doses exposed in the early implantation phase. In breastfeeding, they are not recommended in the first 6 months since estrogens have been shown to reduce milk production and reduce the duration of effective breastfeeding.

Security

Absolute Contraindications (WHO Eligibility Criteria - Category 4)

WHO Medical Eligibility Criteria: Category 4 (Unacceptable Health Risk)

Combined contraceptives are absolutely contraindicated in the presence of:

• Personal history or suspicion of venous thromboembolism (VTE) or active arterial thrombosis (deep vein thrombosis, pulmonary embolism, ischemic stroke or acute myocardial infarction).
• Known thrombogenic mutations (Factor V Leiden, Protein C, Protein S or Antithrombin deficiency, antiphospholipid antibodies).
• Women smokers over 35 years of age who consume 15 cigarettes/day (critical risk of myocardial infarction and stroke).
• Migraine with focused neurological aura at any age (increased risk of ischemic stroke).
• Poorly controlled severe arterial hypertension (SBP > 160 mmHg or DBP > 100 mmHg) or with associated vascular disease.
• Known active estrogen-sensitive neoplasm (breast cancer active or within the last 5 years).
• Active decompensated liver disease (decompensated cirrhosis, liver adenoma or carcinoma).
• Breastfeeding in the first 6 weeks postpartum.

Adverse Effects (ADR)

• Venous thromboembolism (VTE): Ethinyl estradiol stimulates the hepatic synthesis of coagulation factors (Fibrinogen, factor VII, VIII, X) and decreases the synthesis of natural anticoagulants such as protein S, promoting a moderate procoagulant state. Low incidence (~5-12 cases per 10,000 women/year depending on the type of progestogen compared to 2 cases in non-users), but clinically relevant.
• Minor Estrogenic Effects: Nausea, bilateral mastalgia, tension headache, fluid retention and increase in peripheral body weight.
• Intermenstrual bleeding (Spotting): Common in the first 3 months of use due to transient endometrial instability.

Interactions

The administration of potent enzyme inducers of cytochrome CYP3A4 (carbamazepine, phenytoin, phenobarbital, rifampicin, St. John's wort) drastically accelerates the metabolism of COCs, decreasing circulating levels of hormones below the minimum threshold of follicular suppression, causing failure of the contraceptive method. An alternative barrier method of contraception or non-hormonal intrauterine device should be prescribed during and up to 28 days after stopping these drugs.