Endocrine Pharmacology: Oral Contraceptives and Emergency Contraception

Introduction / Overview

Oral contraceptives (OCs) constitute a cornerstone of modern reproductive health, offering reliable, reversible, and relatively low‑cost contraception to millions of women worldwide. Emergency contraception (EC) provides a critical safety net for unintended pregnancies, bridging gaps when standard contraception fails or is unavailable. The clinical relevance of these drug classes is underscored by their widespread use, regulatory scrutiny, and the evolving landscape of patient‑centered care. A thorough understanding of their pharmacologic attributes is essential for clinicians, pharmacists, and other health professionals who counsel patients, prescribe therapies, and manage potential complications.

Learning objectives for this chapter include:

• Describe the classification and chemical characteristics of combined oral contraceptives, progestin‑only pills, and emergency contraceptive agents.
• Explain the pharmacodynamic mechanisms that mediate contraceptive efficacy and potential off‑label benefits.
• Summarize the pharmacokinetic profiles influencing dosing, efficacy, and safety of oral contraceptives and emergency contraception.
• Identify common adverse effects, major drug interactions, and contraindications that guide clinical decision‑making.
• Discuss special patient populations, including pregnant, lactating, pediatric, geriatric, and those with organ dysfunction, in the context of contraceptive therapy.

Classification

Drug Classes and Categories

Oral contraceptives are broadly divided into two main categories:

1. Combined oral contraceptives (COCs) – containing both estrogen and progestin components.
2. Progestin‑only pills (POPs) – containing progestin alone.

Emergency contraception is subdivided into pharmacologic and device‑based approaches:

1. Levonorgestrel (LNG) – a high‑dose progestin.
2. Ulipristal acetate (UPA) – a selective progesterone receptor modulator.
3. Copper intrauterine device (Cu‑IUD) – a non‑hormonal device exerting spermicidal effects.

Chemical Classification

Estrogens employed in COCs are typically ethinyl‑estradiol (EE) or other synthetic analogues with enhanced oral bioavailability. Progestins encompass a spectrum of synthetic derivatives of progesterone, classified by their structural backbone (first‑, second‑, third‑generation) and androgenic or anti‑androgenic activity. UPA is a unique synthetic agent with high affinity for the progesterone receptor but lacking classical progestogenic activity. The copper IUD releases ions that disrupt sperm motility and viability.

Mechanism of Action

Combined Oral Contraceptives

COCs exert their contraceptive effect through multiple, synergistic mechanisms:

• Inhibition of gonadotropin secretion – Estrogen and progestin components suppress luteinizing hormone (LH) surge via negative feedback on hypothalamic‑pituitary‑gonadal (HPG) axis, thereby preventing ovulation.
• Alteration of cervical mucus – Progestin increases mucus viscosity and reduces cervical canal patency, creating a barrier to sperm penetration.
• Endometrial modulation – The hormonal milieu induces decidual changes that render the endometrium less receptive to implantation.
• Potential suppression of follicular growth – Progestin may exert a direct anti‑follicular effect, though this is less pronounced in modern low‑dose formulations.

Progestin‑Only Pills

POPs primarily function through:

• Cervical mucus thickening – Progestin alone increases mucus viscosity, hindering sperm transit.
• Endometrial changes – Progestin induces a denser, less receptive endometrium.
• Possible ovulation suppression – At higher doses or in specific formulations, POPs may inhibit LH surge, but this effect is less reliable than in COCs.

Emergency Contraception – Pharmacologic Agents

Levonorgestrel (LNG) is administered as a single high dose (1.5–2 mg) or divided dose (0.75 mg twice). Its primary action is to delay or inhibit ovulation when given before the LH surge. LNG may also exert post‑ovulatory effects on the endometrium, though this is secondary.

Ulipristal acetate (UPA) is a selective progesterone receptor modulator. By binding with high affinity to the progesterone receptor, UPA modulates the receptor’s conformation, preventing the LH surge and thereby inhibiting ovulation even after the follicle has matured. UPA may also alter the endometrial environment, although the exact contribution remains under investigation.

Emergency Contraception – Device‑Based Approach

The copper IUD (Cu‑IUD) releases copper ions that are toxic to sperm, impairing motility and viability. Additionally, copper induces a localized inflammatory reaction within the endometrium, creating an inhospitable environment for sperm and potential fertilized embryos. The Cu‑IUD can be inserted up to five days post‑coitus, offering a high‑efficacy, long‑term option.

Pharmacokinetics

Absorption

Oral contraceptives are absorbed via the gastrointestinal tract. Estrogens are absorbed rapidly, with peak plasma concentrations reached within 1–2 hours. Progestins exhibit variable absorption; first‑generation progestins often demonstrate lower bioavailability due to extensive first‑pass metabolism. LNG and UPA display high oral bioavailability, with LNG reaching peak concentrations at approximately 1–2 hours post‑dose.

Distribution

Estrogens and progestins are highly protein‑bound (typically >90% to albumin and sex hormone‑binding globulin). This binding influences free drug concentrations and inter‑individual variability. Distribution volumes are moderate, with estrogens achieving higher tissue penetration due to lipophilicity.

Metabolism

CYP450 enzymes, particularly CYP3A4 and CYP2C9, metabolize the majority of steroid hormones. First‑generation progestins undergo extensive hepatic metabolism, whereas second‑ and third‑generation progestins exhibit reduced susceptibility to enzymatic degradation. LNG is metabolized primarily by CYP3A4; UPA is extensively metabolized by CYP3A4 and CYP2C9, producing active metabolites that contribute to its pharmacologic profile.

Excretion

Metabolites are excreted via the kidneys and bile. Estrogen conjugates are predominantly eliminated in feces, whereas progestin metabolites are cleared renally. The elimination half‑life of COCs ranges from 18–48 hours, allowing for once‑daily dosing. LNG has a half‑life of approximately 18 hours, while UPA’s half‑life is around 30 hours, enabling once‑daily dosing for its therapeutic window.

Dosing Considerations

Standard COC regimens involve 21 days of active hormone administration followed by a 7‑day hormone‑free interval, facilitating a withdrawal bleed. POPs are dosed continuously with a 24‑hour interval. LNG EC is administered within 120 hours of unprotected intercourse, with efficacy decreasing beyond 72 hours. UPA EC is indicated up to 120 hours post‑intercourse. The Cu‑IUD offers permanent contraception after insertion, with no pharmacokinetic considerations for hormonal release.

Therapeutic Uses / Clinical Applications

Combined Oral Contraceptives

COCs are primarily indicated for prevention of pregnancy. Off‑label or adjunctive uses include regulation of menstrual cycles, alleviation of dysmenorrhea, treatment of acne vulgaris, and management of pre‑menstrual dysphoric disorder. In certain scenarios, COCs are employed for hormonal suppression in endometriosis and uterine fibroids, though alternative therapies are often preferred.

Progestin‑Only Pills

POPs offer contraceptive efficacy for women who cannot tolerate estrogen, such as those with a history of thromboembolic disease, breast cancer risk, or liver disease. POPs are also suitable for lactating mothers, adolescents, and women with contraindications to estrogen. They provide cycle control, reduce menstrual bleeding, and may benefit patients with endometriosis or dysmenorrhea.

Emergency Contraception

Levonorgestrel and ulipristal acetate are indicated for prevention of pregnancy following unprotected intercourse or contraceptive failure. The Cu‑IUD provides a highly effective, long‑term option immediately after insertion. EC is recommended for women up to 5 days post‑coitus, with reduced efficacy beyond this timeframe. In addition to contraception, EC may help mitigate the psychological distress associated with unintended pregnancy risk.

Adverse Effects

Common Side Effects

Typical adverse effects of COCs include nausea, breast tenderness, headaches, and breakthrough bleeding. POPs may cause irregular bleeding and weight gain in a subset of patients. LNG and UPA EC can provoke nausea, abdominal pain, and menstrual irregularities. The Cu‑IUD may cause cramping, irregular bleeding, and, rarely, uterine perforation or infection.

Serious or Rare Adverse Reactions

Estrogen‑containing contraceptives carry an increased risk of venous thromboembolism (VTE), ischemic stroke, and myocardial infarction, particularly in women with additional risk factors such as smoking, age >35, or thrombophilia. POPs reduce but do not eliminate VTE risk. UPA EC has been associated with transient elevations in liver enzymes and, in rare cases, fulminant hepatic failure. The Cu‑IUD may precipitate pelvic inflammatory disease if inserted during active infection.

Black Box Warnings

COCs are accompanied by a black box warning regarding the risk of thromboembolic events and cardiovascular complications. UPA EC carries a warning for potential severe hepatic injury. Healthcare providers should assess risk factors before prescribing these agents.

Drug Interactions

Major Drug‑Drug Interactions

Enzyme inducers such as rifampin, carbamazepine, phenytoin, and phenobarbital accelerate metabolism of estrogen and progestin, potentially reducing contraceptive efficacy. Conversely, strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir) may increase hormone levels, heightening the risk of adverse effects. Concomitant use of anticoagulants (warfarin, DOACs) may be complicated by estrogen’s influence on coagulation pathways.

Contraindications

Absolute contraindications for estrogen‑containing contraceptives include pregnancy, known or suspected pregnancy, estrogen‑dependent neoplasia, unexplained vaginal bleeding, active thromboembolic disease, and severe hepatic impairment. POPs are contraindicated in pregnancy and certain liver disorders. UPA EC is contraindicated in pregnancy and severe hepatic dysfunction. The Cu‑IUD is contraindicated in active pelvic infection, uterine anomalies, or severe cervical stenosis.

Special Considerations

Use in Pregnancy / Lactation

Oral contraceptives should be discontinued at the onset of pregnancy. POPs are generally considered safe during lactation, with minimal transfer to breast milk; however, the effect on milk production warrants monitoring. COCs may reduce milk supply in some women, though evidence remains inconclusive. UPA EC is contraindicated in pregnancy. The Cu‑IUD is safe during breastfeeding and may be inserted postpartum.

Pediatric / Geriatric Considerations

Oral contraceptives are not approved for use in children under 12; however, adolescents are eligible for COC or POP therapy after appropriate counseling. In older adults, the risk of VTE increases, necessitating thorough cardiovascular risk assessment before prescribing estrogen‑containing contraceptives. POPs may be preferable in geriatric patients due to lower thrombotic risk.

Renal / Hepatic Impairment

Estrogen metabolism is largely hepatic; severe hepatic impairment (Child‑Pugh C) increases hormone levels, potentially elevating adverse event risk. POPs may be safer in hepatic disease, but dose adjustments are rarely required. Renal impairment has minimal impact on hormone clearance, yet patients with end‑stage renal disease should be monitored for fluid balance and bleeding risk. UPA EC is contraindicated in severe hepatic dysfunction, and LNG EC may require dose adjustment in moderate hepatic impairment.

Summary / Key Points

• COCs rely on estrogen‑progestin synergy to inhibit ovulation, alter cervical mucus, and modify the endometrium, while POPs primarily exert effects on mucus and the endometrium.
• Levonorgestrel and ulipristal acetate provide high‑efficacy emergency contraception by delaying ovulation; the copper IUD offers a non‑hormonal, long‑term alternative.
• Pharmacokinetic variability stems from hepatic metabolism via CYP3A4/CYP2C9, with implications for drug interactions and dosing adjustments.
• Risk of thromboembolic events, cardiovascular complications, and hepatic injury necessitates careful patient selection and risk stratification.
• Special populations—including lactating women, adolescents, geriatric patients, and those with organ dysfunction—require individualized assessment to balance efficacy and safety.

Clinical pearls: Consider POPs for patients with estrogen contraindications or lactation; monitor for breakthrough bleeding and weight changes with POP therapy; counsel patients on the importance of timing for EC administration to maximize efficacy; and remain vigilant for drug interactions that may compromise contraceptive protection or increase adverse effects.

References

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