Study Notes on Hormonal Contraceptives

Hormonal Contraceptives

Introduction

  • Presenter: Dr. Bipin

Historical Context

  1. Early 20th Century Contraceptive Methods: Traditional methods included condoms, diaphragms, spermicide creams, and foam tablets, all closely tied to sexual intercourse, which led to their unpopularity among couples.

  2. Failure Rates: These early contraceptive methods exhibited a higher failure rate.

  3. Revolution in Contraception: In 1955, Rock and Pincus announced the successful use of oral progestin for contraception, effectively separating fertility control from the act of intercourse.

  4. Estrogen Addition: It was later discovered that adding a small quantity of estrogen to progestins significantly enhanced contraceptive efficacy. Consequently, combined hormonal contraceptive pills became widely popular due to reduced hormone content, minimized potential harm, and additional health benefits associated with their use.

Types of Contraceptives

  • Male Condom

  • Combined Oral Contraceptive Pill

  • Vaginal Ring

  • Progestogen-only Pill

  • Contraceptive Injection

  • Diaphragm

  • Hormonal Intrauterine Device (IUD)

  • Contraceptive Implant

  • Copper Intrauterine Device (IUD)

Female Contraception Overview

  1. Usage Statistics: Over 100 million women globally are currently using hormonal contraceptives.

  2. Fertility Control: These drugs allow women to suppress fertility intentionally and reliably, with nearly 100% confidence, and permit complete return of fertility upon discontinuation.

  3. Advantages of Oral Contraceptives (OCs): Their efficacy, convenience, low cost, and overall safety empower women to make informed decisions regarding pregnancy timing and to plan their activities effectively.

  4. Variety of Preparations: A diverse selection of oral and parenteral contraceptive preparations exists, providing women with personalized choices.

Oral Contraceptives: Combined Pill

Characteristics

  1. Composition: A fixed dose of an estrogen and progestin taken throughout a treatment cycle (monophasic).

  2. Dosage Reduction: With growing experience, the doses of estrogen and progestin have been reduced in 'second generation' OCs without efficacy loss, minimizing side effects and complications.

  3. Third Generation: The introduction of third-generation pills in the 1990s featuring newer progestins like desogestrel has improved their action profile.

  4. Threshold Dosage: Ethinyl estradiol at 30 µg daily is considered the threshold dose, which can be lowered to 20 µg/day if a potent antiovulatory progestin is utilized.

Table 22.2: Oral Contraceptive Preparations

  • Combined Pills

    1. Norgestrel

      • Progestin: 0.3 mg

      • Estrogen: Ethinylestradiol 30 μg

    2. Norgestrel

      • Progestin: 0.5 mg

      • Estrogen: Ethinylestradiol 50 μg

    3. Levonorgestrel

      • Progestin: 0.25 mg / 0.1 mg

      • Estrogen: Ethinylestradiol 50 μg / 20 μg

    4. Desogestrel

      • Progestin: 0.15 mg

      • Estrogen: Ethinylestradiol 30 μg / 20 μg

Progestin Efficacy

  1. Progestin Mechanism: The progestin used in OCs is a 19-nortestosterone, recognized for its potent anti-ovulatory action.

  2. Ovulation Inhibition: Estimated daily doses needed to inhibit ovulation when using progestins alone are as follows:

    • Levonorgestrel: 60 µg

    • Desogestrel: 60 µg

    • Norgestimate: 200 µg

    • Gestodene: 40 µg

    • Higher doses are present in the pill for 100% certainty.

Phased Pill

  1. Triphasic Regimens: Introduced to minimize overall steroid dosage while maintaining efficacy, these pills mimic hormonal patterns of a natural menstrual cycle.

  2. Dosage Structure: The estrogen dose remains constant (slightly varied at 30–40 µg), while progestin amounts start low and increase through the cycle.

  3. Recommendations: Phasic pills are particularly advised for women over 35 or those with previous issues on monophasic pills.

  4. Efficacy Evidence: Evidence supporting the superiority of triphasic over monophasic pills is limited.

Progestin-Only Pill (Minipill)

  1. Estrogen Elimination: Designed to remove estrogen to mitigate associated long-term risks.

  2. Usage Instructions: Taken daily without breaks; menstruation tends to be irregular and ovulation can occur in 20-30% of women. Other mechanisms like hostile cervical mucus contribute to contraception.

  3. Efficacy Rate: Declared efficacy rates range from 96-98%, which is lower compared to 98-99.9% for combined pills.

  4. Pregnancy Monitoring: Women should suspect pregnancy if amenorrhea exceeds two months; this method is not widely favored.

Emergency (Postcoital) Pill

  1. Purpose: For use in women not currently using contraception after unprotected intercourse.

  2. Standard Regimen: The most common protocol involves administering Levonorgestrel 0.75 mg in two doses 12 hours apart or a single 1.5 mg dose, ideally within 72 hours.

  3. Efficacy Improvement: Trials showed this regimen to be 2-3 times more effective than previous ones, which included levonorgestrel 0.5 mg with ethinylestradiol.

Injectable Contraceptives

Overview

  1. Contraceptive Development: Injectable methods emerged to eliminate the daily pill regimen.

  2. Administration: Injectables are given intramuscularly (IM) as oily solutions and have been used by over 50 million women.

  3. Carcinogenic Potential: Though animal studies suggest carcinogenic risks, studies on humans over 30 years show no overarching cancer risk, especially for cervical, ovarian, or hepatic cancers.

  4. Additional Risks: Slightly increased breast cancer risk has been observed in younger women under 35.

  5. Logistical Challenges: Practical administration issues in developing countries and lower field effectiveness remain significant barriers.

Types of Injectable Contraceptives

  1. Depot Medroxyprogesterone Acetate (DMPA): 150 mg given at 3-month intervals; peak blood levels reached 3 weeks post-injection with a half-life of approximately 50 days.

    • Label: DEPOT-PROVERA 150 mg for deep IM injection initiated during the first 5 days of the menstrual cycle, to be repeated every three months.

  2. Norethindrone (Norethisterone) Enanthate: 200 mg every 2 months; labeled as NORISTERAT for IM injection within the menstrual cycle's first 5 days.

Effectiveness of Hormonal Contraceptives

Comprehensive Overview Table 22.3: Effects of Different Forms

Type of Hormonal Contraceptive

FSH Inhibition

LH Inhibition

Antiovulatory Effect

Hostile Cervical Mucus

Endometrial Changes

Failure Rate (Perfect Use)

Contraceptive Efficacy

Combined (E+P) Oral Pills

++

+++

+++

+++

Hypersecretory

0.3%

++++

Progestin-only P

+

+

+

+++

Out of phase

2-3%

+++

Postcoital only P

+

-

+

++

Atrophic

< 0.5%

++++

Injections

++++

++

+++

+++

Unfavourable

2-4%

++

Mechanism of Action of Hormonal Contraceptives

  1. Primary Mechanism: Hormonal contraceptives primarily operate through negative feedback on the hypothalamus and pituitary, inhibiting the release of GnRH, FSH, and LH, preventing ovulation.

  2. Role of Progestin: Progestin is crucial not only for ovulation suppression but also for thickening cervical mucus and thinning the endometrium, making it less receptive to implantation.

  3. Estrogen's Role: In combination methods, estrogen stabilizes the endometrium and reduces breakthrough bleeding, while enhancing the effects of progestin.

  4. Efficacy Rates: The failure rates with perfect use are very low (<1%). However, typical use aligns with approximately 9% failure rates for oral contraceptives due to real-world inconsistencies.

Classifications of Oral Contraceptive Pills (OCP)

  1. Monophasic: Fixed hormone dose across all pills in a pack.

  2. Multiphasic: Variations in dosages to mimic the natural hormonal cycle.

  3. Cyclic: 21-24 active pills followed by 4-7 placebo pills for monthly withdrawal bleeding.

  4. Extended-Cycle: 84 active pills followed by 1 week of placebo, allowing for only four withdrawals annually.

  5. Continuous-Use: No placebo pills, taken every day, foregoing scheduled withdrawal bleeding.

Indications for OCP

  • Primary Indication: Prevention of pregnancy.

  • Non-Contraceptive Benefits: Managing menstrual disorders (pain, irregular bleeding), alleviating endometriosis-related pain, treating acne (FDA-approved for certain brands), and hirsutism. Long-term use significantly lowers the risk of ovarian and endometrial cancer.

Mechanism of Action of OCPs

  1. Ovulation Suppression: The synergistic action of estrogen and progestin provides strong feedback inhibition on GnRH, FSH, and LH, preventing follicular growth and the LH surge.

  2. Cervical Mucus Changes: Progestin thicken cervical mucus, causing difficulties for sperm penetration.

  3. Endometrial Dynamics: Progestin makes the endometrial lining less favorable for embryo implantation.

Dosing and Drug Interactions

  1. Common Dosage: Most low-dose OCPs include between 10-35 mcg of ethinyl estradiol (EE). Older, high-dose formulations often contain 50 mcg or more, though their use is rare due to higher side effects.

  2. Alternatives: Some newer formulations utilize body-identical estrogens like estradiol valerate or estetrol, not directly interchangeable with EE in doses.

  3. Drug Interactions: Certain antibiotics and liver enzyme-inducing drugs (e.g., rifampin, specific anticonvulsants like phenytoin) can decrease the efficacy of combined oral contraceptives. It is essential to advise usage of backup non-hormonal methods like condoms during concurrent medication use.

Side Effects and Contraindications of OCPs

  1. Common Side Effects: Include nausea, bloating, breast tenderness, headaches, melasma (facial pigmentation) due predominantly to estrogen, and - for progestin - acne, mood changes, weight fluctuations.

  2. Serious Risks: Include heightened risks of venous thromboembolism (VTE), stroke, and myocardial infarction, particularly in women with predisposed risk factors. The highest risk appears during the first year of use.

  3. Contraindications: Based on the mnemonic "ACHES":

    • Age ≥35 and smoker

    • Hypertension (systolic ≥160 or diastolic ≥100) or vascular disease

    • History of/current DVT/PE or known thrombophilia (e.g., Factor V Leiden)

    • Migraine with aura (increased stroke risk)

    • Breast cancer (current)

    • Severe liver disease

    • Pregnancy

    • Postpartum <21 days (increased clotting risk).

Progestin-Only Pills (Minipill)

Overview and Features

  1. Composition: Contains only progestin, e.g., Norethindrone 0.35 mg, Drospirenone 4 mg, with all active pills without placebo.

  2. Indications: Mainly utilized for women contraindicated to estrogens or those who are postpartum.

  3. Mechanism: Primarily functions by thickening cervical mucus and occasionally inhibiting ovulation. This mechanism's effectiveness requires diligent adherence to dosing schedules.

Dosing and Interaction Considerations

  1. Dosing Guidelines: Must be taken at the same time every day; a delay exceeding 3 hours mandates backup contraception usage for 48 hours.

  2. Interactions: Similar enzyme-inducing drugs impacting OCP efficacy will also reduce Minipill effectiveness.

Contraindications and Side Effects

  1. Contraindications: Current breast cancer, unexplained vaginal bleeding, severe cirrhosis, and history of ischemic heart disease are notable exclusions.

  2. Side Effects: Irregular menstrual bleeding is the most common complication, with potential for functional ovarian cysts but minimal risk of VTE due to absence of estrogen effects.

Injectable Contraceptives Overview

Features and Classifications

  1. Description: Long-lasting injectable forms of progestin-only contraception, including Depot Medroxyprogesterone Acetate (DMPA).

  2. Indications: Effective for pregnancy prevention, suitable for women desiring a long-term solution without daily adherence to a regimen.

  3. Mechanism: Suppresses follicular activity through gonadotropin inhibition and thickens cervical mucus as a barrier against sperm.

Dosing Recommendations

  1. Dosing: Standard is 150 mg IM or 104 mg SC every 12-13 weeks.

  2. Interactions: Efficacy generally unaffected by enzyme-inducing drugs, but caution is recommended.

Contraindications and Side Effects

  1. Contraindications: Includes multiple risk factors for cardiovascular disease and history of ischemic heart disease or stroke.

  2. Side Effects: Potential delayed return to fertility, bone mineral density loss with prolonged use, and common weight gain or mood changes.

Implantable Hormonal Contraceptives

Overview

  1. Etonogestrel Implant (Nexplanon): Thin, flexible rod implanted subdermally.

  2. Indications: Effective long-term contraceptive option for those who prefer a non-daily method.

  3. Mechanism: Similar to other hormonal methods, it mainly inhibits ovulation.

Dosing Schedule

  1. Dosing: Effective for up to 3 years post-implantation, necessitating removal or replacement afterward.

  2. Interactions and Cautions: Subject to the same interactions as other forms constrained by enzyme-inducers.

Side Effects

  • Frequent irregular menstrual bleeding is the top cause for discontinuation, along with reactions at the insertion site such as pain or scarring.

Initiation of Contraceptive Methods

  1. Quick Start Rule: A woman may start contraception at any time if not likely pregnant. If initiated within the first 5 days of the menstrual cycle, backup is unnecessary; if later, backup is required for 7 days for OCPs/POPs.

  2. Postpartum Considerations:

    • OCPs: Should not be started within 21 days postpartum due to VTE risk; for breastfeeding mothers, wait 42 days as estrogen affects milk supply.

    • POPs/Implants/Injections: Can be initiated immediately postpartum, being safe for breastfeeding women.

Risk Factors and Considerations

  1. VTE Risk Evaluations: Although hormonal contraceptives containing estrogen elevate VTE risks, the absolute risk remains low when compared with incidences during pregnancy and postpartum.

  2. Antibiotics and Efficacy: Standard antibiotics do not typically interfere with hormonal contraceptive efficacy; however, potent inducers like Rifampin notably do.

  3. Non-Contraceptive Advantages: Hormonal contraceptives, specifically OCPs, confer protective effects against certain cancers and help in managing conditions like acne and dysmenorrhea, advantageous effects persisting well beyond cessation.

Conclusion

  • Hormonal contraceptives have revolutionized sexual and reproductive health, offering a variety of options to empower individuals in their family planning. Understanding their mechanisms, efficacy, and implications helps in making informed decisions regarding reproductive choices.

Acknowledgements

  • Thank you for your attention!