Pharmacology of Hormonal Contraceptives

1. Introduction/Overview

Hormonal contraceptives represent a cornerstone of modern reproductive medicine, providing highly effective and reversible fertility control. These pharmaceutical agents, which utilize synthetic derivatives of endogenous sex steroids, are among the most extensively studied and widely prescribed medications globally. Their development and refinement over the past six decades have transformed family planning, contributing significantly to public health by reducing unintended pregnancies and enabling individuals to exercise autonomy over reproductive timing. Beyond their primary contraceptive indication, many hormonal contraceptive formulations possess additional therapeutic benefits, including management of menstrual disorders, acne, and endometriosis, thereby occupying a multifaceted role in clinical practice.

The clinical relevance of hormonal contraceptives is profound, with utilization spanning adolescence through perimenopause. A thorough understanding of their pharmacology is essential for healthcare providers to ensure safe, effective, and individualized prescribing. This knowledge encompasses not only the mechanisms underlying contraceptive efficacy but also the pharmacokinetic principles governing dosing regimens, the spectrum of potential adverse effects, and critical interactions with concomitant medications. Mastery of this topic allows clinicians to counsel patients accurately, manage side effects, and mitigate risks, particularly those associated with thromboembolic events.

Learning Objectives

Upon completion of this chapter, the reader should be able to:

• Classify the major types of hormonal contraceptives based on their composition, route of administration, and hormonal activity.
• Explain the primary and secondary mechanisms of action by which combined estrogen-progestin and progestin-only contraceptives prevent pregnancy.
• Describe the pharmacokinetic profiles of key estrogenic and progestogenic components, including absorption, metabolism, and elimination pathways.
• Identify the common and serious adverse effects associated with hormonal contraceptive use, with particular attention to cardiovascular risks.
• Analyze significant drug-drug interactions involving hormonal contraceptives, especially those mediated by hepatic enzyme induction, and apply this knowledge to clinical management.

2. Classification

Hormonal contraceptives are systematically classified according to their hormonal composition, dosage regimen, and route of administration. The fundamental division is between combined hormonal contraceptives (CHCs), containing both an estrogen and a progestin, and progestin-only contraceptives (POCs).

2.1. Combined Hormonal Contraceptives (CHCs)

These products synergistically utilize an estrogen and a progestin. The estrogen component is almost exclusively ethinyl estradiol (EE), a synthetic steroid with high oral bioavailability and prolonged half-life due to ethinylation at the 17α position. Mestranol, an early pro-drug of EE, is now rarely used. The progestin component varies considerably and defines many product characteristics. Progestins are categorized by generation, reflecting their historical development and androgen receptor affinity.

• First-generation: Norethindrone (norethisterone), norethindrone acetate, ethynodiol diacetate. These are derived from 19-nortestosterone and possess modest androgenic activity.
• Second-generation: Levonorgestrel, norgestrel. These are more potent and exhibit higher androgenic activity.
• Third-generation: Desogestrel, norgestimate, gestodene. Developed to reduce androgenic side effects, these have increased selectivity for the progesterone receptor. Desogestrel and norgestimate are metabolized to active compounds (etonogestrel and levonorgestrel, respectively).
• Fourth-generation and other: Drospirenone (a spironolactone analogue with anti-mineralocorticoid activity), dienogest (with antiandrogenic properties), and nomegestrol acetate.

CHCs are further sub-classified by administration route:

1. Oral Combined Contraceptives (COCs): Monophasic (fixed dose), biphasic, triphasic (varying doses across cycle), and extended-cycle (84 active days) formulations.
2. Transdermal Patch: Delivers norelgestromin (active metabolite of norgestimate) and EE.
3. Vaginal Ring: Delivers etonogestrel (active metabolite of desogestrel) and EE.

2.2. Progestin-Only Contraceptives (POCs)

These formulations contain no estrogen, making them suitable for individuals with contraindications to estrogen. They are classified by route and duration of action.

• Oral (Progestin-Only Pill, “mini-pill”): Contains norethindrone or drospirenone (in some regions) or desogestrel (75 µg, which is anti-ovulatory).

Long-Acting Reversible Contraceptives (LARCs):

• Subdermal Implant: Etonogestrel or levonorgestrel rods providing 3-5 years of efficacy.
• Intrauterine System (IUS): Levonorgestrel-releasing intrauterine device, providing 3-8 years of efficacy.
• Injectable: Depot medroxyprogesterone acetate (DMPA) administered intramuscularly or subcutaneously every 3 months.

3. Mechanism of Action

The contraceptive efficacy of hormonal agents is achieved through a multi-faceted suppression of the hypothalamic-pituitary-ovarian (HPO) axis and alteration of the reproductive tract environment. The primary mechanisms differ between combined and progestin-only products.

3.1. Combined Hormonal Contraceptives

The mechanism of CHCs is predominantly central, mediated through negative feedback inhibition.

• Suppression of Gonadotropin Secretion: The exogenous estrogen and progestin act on hypothalamic gonadotropin-releasing hormone (GnRH) neurons and pituitary gonadotrophs. Estrogen suppresses follicle-stimulating hormone (FSH) secretion, inhibiting follicular recruitment and development. The progestin component potently suppresses the mid-cycle luteinizing hormone (LH) surge, which is absolutely required for ovulation. The absence of this LH surge prevents follicular rupture and ovulation. This is considered the primary mechanism of action for CHCs.
• Endometrial Changes: Progestins induce a decidualization of the endometrial stroma and glandular atrophy. This results in a thin, unreceptive endometrium that is unsuitable for blastocyst implantation.
• Cervical Mucus Alteration: Progestins thicken cervical mucus, increasing its viscosity and decreasing its elasticity. This forms a hostile, impenetrable barrier to sperm ascent into the uterine cavity.
• Alteration of Tubal Motility: There may be subtle effects on fallopian tube peristalsis, potentially affecting ovum and embryo transport.

3.2. Progestin-Only Contraceptives

The dominant mechanism varies with the dose and formulation of the progestin.

• Low-Dose Oral POCs (e.g., norethindrone 350 µg): Ovulation inhibition is inconsistent (~40-60% of cycles). The primary mechanism is cervical mucus thickening, creating an effective sperm barrier. Endometrial changes also contribute to efficacy.
• Higher-Dose Oral POCs (e.g., desogestrel 75 µg): These reliably suppress ovulation in most cycles, similar to CHCs but without an estrogen component.
• Long-Acting Progestins (Implant, IUS, Injectable): These potently suppress the HPO axis, leading to consistent anovulation. The levonorgestrel-IUS exerts a strong local effect on the endometrium, causing profound glandular suppression and stromal decidualization, which is its major contraceptive mechanism, especially at lower doses. DMPA and implants provide sustained systemic progestin levels that inhibit ovulation and produce cervical and endometrial effects.

All hormonal contraceptives act prior to implantation; they are not abortifacients. They do not disrupt an established pregnancy.

4. Pharmacokinetics

The pharmacokinetic properties of hormonal contraceptives are complex, influenced by the specific steroids used, their formulation, and the route of administration.

4.1. Absorption and Bioavailability

Ethinyl Estradiol (EE): Following oral administration, EE is rapidly and extensively absorbed from the gastrointestinal tract. However, it undergoes significant first-pass metabolism in the gut wall and liver, primarily via sulfation and cytochrome P450 (CYP) 3A4-mediated hydroxylation, resulting in an oral bioavailability of approximately 40-50%. Absorption is enhanced when taken with food. Transdermal and vaginal routes bypass first-pass metabolism, providing more stable serum concentrations.

Progestins: Most synthetic progestins (e.g., norethindrone, levonorgestrel) are well absorbed orally with high bioavailability (60-100%). Some, like norgestimate and desogestrel, are prodrugs requiring hepatic conversion to their active metabolites (levonorgestrel and etonogestrel, respectively). Non-oral routes provide sustained, zero-order delivery. For example, the subdermal implant releases etonogestrel at a rate of 40-70 µg/day initially, declining over time, while the levonorgestrel-IUS releases 20 µg/day (or lower, depending on the model) directly into the uterine cavity.

4.2. Distribution

Steroid hormones are highly lipophilic and distribute widely into body fat. They are extensively bound to plasma proteins. EE is approximately 98% bound, primarily to albumin. Synthetic progestins bind with high affinity to sex hormone-binding globulin (SHBG); binding affinity varies (e.g., levonorgestrel > norethindrone). EE increases hepatic synthesis of SHBG, which can alter the free fraction of co-administered progestins. The volume of distribution for these compounds is large, often exceeding 1 L/kg.

4.3. Metabolism

Metabolism is primarily hepatic and involves Phase I (oxidation, reduction) and Phase II (conjugation) reactions.

• EE Metabolism: Major pathways include 2-hydroxylation (CYP2C9, 3A4) followed by methylation, and 16α/β-hydroxylation. It also undergoes enterohepatic recirculation; conjugates excreted in bile are hydrolyzed by gut bacteria, and free EE is reabsorbed. Antibiotics that alter gut flora may theoretically disrupt this recirculation.
• Progestin Metabolism: Pathways include reduction of the 3-keto group, hydroxylation at various positions (mediated by CYP3A4, 2C19), and conjugation. Norethindrone is metabolized to reduced and hydroxylated metabolites. Levonorgestrel is metabolized primarily by reduction and conjugation.

Metabolic clearance can be significantly induced or inhibited by concomitant medications, a critical consideration for drug interactions.

4.4. Excretion

Metabolites are excreted primarily in urine (60-80%) and feces (20-40%) as glucuronide and sulfate conjugates. The parent compounds are not excreted unchanged. The elimination half-life (t_1/2) is formulation-dependent but generally ranges from 5-30 hours for orally administered steroids. EE has a t_1/2 of approximately 15-30 hours. Levonorgestrel’s t_1/2 is about 12-20 hours. For long-acting methods, the release rate, not the elimination t_1/2, governs the duration of action. After removal of an implant or IUS, serum levels fall rapidly, and ovulation typically returns within weeks to a few months. The return of fertility after DMPA discontinuation may be delayed for 9-12 months on average due to persistent depot effects.

5. Therapeutic Uses/Clinical Applications

5.1. Approved Contraceptive Indications

The primary indication for all hormonal contraceptives is the prevention of pregnancy. Efficacy is expressed as the Pearl Index (failures per 100 woman-years). Long-acting reversible contraceptives (LARCs) have the highest efficacy (failure rate <1%), followed by correctly used CHCs and POCs (~0.3% and ~0.5-4% respectively, depending on adherence). Typical use failure rates are higher for user-dependent methods like pills.

5.2. Non-Contraceptive Benefits

Hormonal contraceptives are frequently prescribed for therapeutic benefits beyond fertility control.

• Menstrual Cycle Regulation: Reduction of dysmenorrhea, menorrhagia, and irregular bleeding. Extended-cycle regimens can reduce the frequency of withdrawal bleeds.
• Treatment of Ovulation-Related Disorders: Management of premenstrual dysphoric disorder (PMDD) and mittelschmerz.
• Androgen-Dependent Conditions: Improvement of acne vulgaris and hirsutism, particularly with formulations containing antiandrogenic progestins (e.g., drospirenone, dienogest) or those with low androgenic activity.
• Endometriosis and Chronic Pelvic Pain: Used to suppress ectopic endometrial tissue growth and associated pain.
• Benign Gynecologic Conditions: Reduction of symptoms from uterine leiomyomas (fibroids) and adenomyosis.
• Risk Reduction: Decreased risk of ovarian cancer (up to 50% reduction with 5 years of use), endometrial cancer (up to 50% reduction), ectopic pregnancy, and pelvic inflammatory disease.

6. Adverse Effects

Adverse effects range from common, benign side effects to rare, serious complications. The risk profile differs between CHCs and POCs.

6.1. Common Side Effects

These are often related to the hormonal milieu and may attenuate after the first few cycles.

• Estrogen-related: Nausea, breast tenderness, bloating, headaches.
• Progestin-related: Androgenic effects (acne, weight gain, mood changes with some progestins), fatigue.
• Breakthrough Bleeding and Spotting: Particularly common during the first 3 months of use with all methods, as the endometrium adjusts. More frequent with POCs and low-dose CHCs.
• Amenorrhea: Common with long-acting progestins (DMPA, implant, IUS) and extended-cycle COCs, and is not harmful.

6.2. Serious Adverse Reactions

These events, while uncommon, necessitate careful patient selection and counseling.

• Venous Thromboembolism (VTE): The most significant pharmacovigilance concern for CHCs. EE induces a dose-dependent increase in hepatic synthesis of clotting factors (II, VII, VIII, X, fibrinogen) and decreases anticoagulant factors (antithrombin, protein S). This creates a prothrombotic state. The baseline absolute risk in reproductive-aged women not using CHCs is about 2-5 per 10,000 woman-years. CHC use increases this risk 3-6 fold. Risk is highest in the first year of use and with higher EE doses. Some data suggest a slightly higher risk with third- and fourth-generation progestins (e.g., desogestrel, drospirenone) compared to levonorgestrel, though the absolute risk difference is small. POCs do not increase VTE risk.
• Arterial Thromboembolism: Increased risk of myocardial infarction and ischemic stroke, particularly in women over 35 who smoke or have other cardiovascular risk factors (hypertension, diabetes, migraine with aura).
• Hypertension: EE can cause a mild increase in blood pressure via activation of the renin-angiotensin-aldosterone system.
• Hepatic Effects: Benign hepatic adenomas and rare hepatocellular carcinoma are associated with long-term, high-dose use. Cholestatic jaundice may occur in susceptible individuals.
• Gallbladder Disease: Increased risk of cholelithiasis due to estrogen-induced changes in bile composition.
• Cervical Cancer: Long-term CHC use (≥5 years) is associated with a modestly increased relative risk of cervical cancer, possibly related to behavioral factors (persistent HPV infection).
• Breast Cancer: A small increased relative risk has been observed in current and recent users of hormonal contraceptives, which diminishes after discontinuation and approaches that of never-users after about 10 years. The absolute increase in risk is considered very small.
• Bone Mineral Density (BMD): DMPA use is associated with a reversible reduction in BMD due to profound estrogen suppression. This is a particular concern for adolescents and perimenopausal women. Other methods do not significantly affect BMD.

7. Drug Interactions

Drug interactions are a major clinical consideration, as they can compromise contraceptive efficacy or exacerbate adverse effects.

7.1. Interactions Reducing Contraceptive Efficacy

The most critical interactions involve induction of hepatic drug-metabolizing enzymes.

• Hepatic Enzyme Inducers: Drugs that induce CYP3A4 (and possibly UDP-glucuronosyltransferases) accelerate the metabolism of both EE and synthetic progestins, potentially leading to breakthrough ovulation and contraceptive failure. Key inducers include:
  • Anticonvulsants: Carbamazepine, phenytoin, phenobarbital, primidone, topiramate (at higher doses), oxcarbazepine.
  • Antimicrobials: Rifampicin, rifabutin (potent inducers). Griseofulvin.
  • Antiretrovirals: Efavirenz, nevirapine, ritonavir-boosted protease inhibitors (complex effects).
  • Others: Modafinil, St. John’s wort (Hypericum perforatum).

  Concomitant use typically necessitates a higher-dose CHC (≥50 µg EE, though not always effective) or, more reliably, a non-hormonal or LARC method.

• Antibiotics (excluding rifamycins): Broad-spectrum antibiotics (e.g., penicillins, tetracyclines) are commonly believed to reduce efficacy by disrupting enterohepatic recirculation of EE. Evidence for this interaction causing pregnancy is weak and controversial. Nevertheless, caution is advised, and backup contraception is often recommended during and for 7 days after antibiotic therapy.

7.2. Interactions Potentiating Adverse Effects or Affecting Other Drugs

• Drugs increasing serum potassium: Drospirenone has anti-mineralocorticoid activity and can raise serum potassium. Concomitant use with potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs, or heparin requires monitoring, particularly in patients with renal or adrenal insufficiency.
• Effect of CHCs on Other Drugs: EE can inhibit certain CYP enzymes (e.g., CYP1A2). This may increase plasma concentrations of drugs like theophylline, tizanidine, and some benzodiazepines. EE-induced increases in SHBG can decrease the free fraction of corticosteroids and thyroid hormones, potentially altering dose requirements.

7.3. Contraindications

Absolute contraindications to estrogen-containing contraceptives (based on WHO Medical Eligibility Criteria) include:

1. Current or history of venous or arterial thromboembolism.
2. Known thrombogenic mutations (e.g., Factor V Leiden, prothrombin mutation).
3. Major surgery with prolonged immobilization.
4. Current or history of ischemic heart disease or cerebrovascular accident.
5. Complicated valvular heart disease.
6. Uncontrolled hypertension (≥160/100 mmHg).
7. Migraine with aura at any age.
8. Current or history of breast cancer.
9. Diabetes with vascular complications (nephropathy, retinopathy, neuropathy).
10. Severe cirrhosis, hepatocellular adenoma, or malignant hepatoma.
11. Undiagnosed abnormal genital bleeding.
12. Pregnancy.

Progestin-only methods are generally safe in most of these conditions, except for current breast cancer. DMPA is contraindicated in women with significant risk factors for osteoporosis.

8. Special Considerations

8.1. Use in Pregnancy and Lactation

Pregnancy (Category X): Hormonal contraceptives are contraindicated during pregnancy. However, extensive epidemiological data have not demonstrated an increased risk of major congenital malformations (“birth defects”) following accidental exposure during early pregnancy. If pregnancy is confirmed, the contraceptive should be discontinued immediately.

Lactation: Estrogen can suppress milk production and reduce protein and fat content. Therefore, CHCs are not recommended during the first 6 weeks postpartum and should be used with caution in breastfeeding women. Progestin-only methods are preferred as they do not affect milk supply and may even increase it. Minimal amounts of progestins are excreted in breast milk, but no adverse effects on infant growth or development have been demonstrated with any POC, including DMPA and implants.

8.2. Pediatric and Adolescent Considerations

Hormonal contraceptives are safe and effective for adolescents. LARCs are considered first-line due to their high efficacy and lack of user adherence requirements. Bone health should be considered with DMPA use in adolescents; the BMD loss is usually reversible upon discontinuation, but alternative methods may be preferred if other risk factors for osteoporosis exist.

8.3. Geriatric Considerations

In perimenopausal women, the benefits of contraception and cycle control must be weighed against increasing cardiovascular risk with age. CHCs are generally contraindicated in women over 35 who smoke. For healthy, non-smoking women over 35 without other contraindications, low-dose CHCs may be used until menopause (age 50-55). Progestin-only methods are often excellent alternatives. Hormonal contraceptives do not delay the onset of menopause.

8.4. Renal and Hepatic Impairment

Renal Impairment: Mild to moderate impairment does not preclude use. In severe renal impairment or renal failure, CHCs should be avoided due to increased hypertension and thrombosis risk. Drospirenone is contraindicated in renal impairment due to its antimineralocorticoid effects and risk of hyperkalemia.

Hepatic Impairment: Hormonal contraceptives are metabolized by the liver. Their use is contraindicated in acute viral hepatitis, severe cirrhosis (Child-Pugh B or C), and all hepatic tumors. In mild, compensated chronic liver disease, progestin-only methods may be considered safer than CHCs, as they lack the estrogenic effects on hepatic protein synthesis.

9. Summary/Key Points

• Hormonal contraceptives are classified as combined (estrogen + progestin) or progestin-only, with further subdivision by route (oral, transdermal, vaginal, injectable, implantable, intrauterine).
• The primary mechanism of combined methods is suppression of the hypothalamic-pituitary-ovarian axis, inhibiting the LH surge and ovulation. Progestin-only methods rely on a dose-dependent combination of ovulation suppression, cervical mucus thickening, and endometrial changes.
• Ethinyl estradiol undergoes significant first-pass metabolism, while most synthetic progestins have high oral bioavailability. Metabolism is primarily hepatic via CYP enzymes, particularly CYP3A4.
• Non-contraceptive benefits include treatment of dysmenorrhea, menorrhagia, acne, endometriosis, and significant reductions in ovarian and endometrial cancer risk.
• The most serious adverse effect of combined contraceptives is venous thromboembolism, with risk influenced by estrogen dose, progestin type, and patient factors (age, smoking, obesity). Progestin-only methods do not increase VTE risk.
• Potent hepatic enzyme inducers (e.g., rifampin, certain anticonvulsants, St. John’s wort) can significantly reduce contraceptive hormone levels and efficacy, necessitating alternative contraceptive strategies.
• Estrogen-containing contraceptives are contraindicated in numerous conditions, primarily related to thrombotic risk. Progestin-only methods have far fewer contraindications and are preferred in many special populations, including breastfeeding women.

Clinical Pearls

• For maximum effectiveness, patient-centered counseling is crucial. Long-acting reversible contraceptives (implants and IUSs) have the highest efficacy and continuation rates.
• When prescribing for a woman on a potent enzyme-inducing drug, a CHC containing ≥50 µg of ethinyl estradiol may be considered, but breakthrough bleeding is common and efficacy is not guaranteed. A LARC or alternative non-hormonal method is often the most reliable choice.
• The progestin-only pill containing desogestrel 75 µg has a 12-hour missed-pill window, similar to CHCs, whereas the traditional norethindrone mini-pill has a strict 3-hour window before backup contraception is advised.
• Unscheduled bleeding in the first 3 months of use is common and often self-limiting. Persistent bleeding beyond this point may be managed by switching to a formulation with a different progestin or a slightly higher estrogen dose.
• Before initiating a CHC, a focused history should screen for contraindications, with particular attention to personal or family history of thrombosis, migraine aura, hypertension, and smoking status.

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