I. Estrogen Receptor Agonists and Mixed Estrogen and Progesterone Agonists
A. Combination Oral Contraceptives (COCs)
Estrogens:
Ethinyl Estradiol: A synthetic derivative of estrogen.
Estetrol: A natural estrogen from human fetal liver; its profile indicates less blood clotting effects as it has a higher affinity for Estrogen Receptor α (ERα) than Estrogen Receptor β (ERβ).
Transdermal Systems & Vaginal Rings: Delivery methods that avoid first-pass metabolism and can be effectively combined with progesterone.
B. Synthetic Progesterones (Progestins)
Common Progestins Include:
Levonorgestrel
Desogestrel
Norgestimate
Drospirenone
Norethindrone
Approval Notes:
Norethindrone: Commonly prescribed, sometimes referred to as Nor-Q.D.
Norgestrel: Available without prescription/OTC.
Medroxyprogesterone Acetate: Delivered SubQ; noted adverse effect includes brain tumors.
Etonogestrel: This form is implanted under the skin and is used for contraceptive purposes.
Emergency Contraceptives
Levonorgestrel: Doses of 1.5 mg available in Plan B® kit.
Ulipristal: Another emergency contraceptive option.
Intrauterine Devices (IUDs)
Types:
Copper IUD
Levonorgestrel IUD
Usage Duration: Can be left in place for several years.
II. COCs Breakdown
Defined as a combination of synthetic estrogen and synthetic progestin.
Dosage Patterns: 21 days of active pills followed by 7 days without (often supplemented with ferrous).
Types of COCs:
Monophasic: Fixed dosage of estrogen and progestin every day (e.g., Ethinyl estradiol (20μg) + Levonorgestrel).
Multiphasic: Hormone levels mimic the normal menstrual cycle with varying doses throughout the cycle, resulting in less hormone exposure.
Biphasic: Estrogen remains constant with progestin levels that change twice.
Triphasic: And both compounds may vary in dosage three times during the cycle. E.g., Ethinyl estradiol 25µg + Desogestrel 0.1mg.
Four-Phasic: Doses vary four times throughout the cycle.
Start Date for COCs:
First Day of Menses: Allows for more rapid contraception.
First Sunday after Menses: Requires backup contraception for 7 days.
III. Chemistry & Pharmacokinetics of Estrogens
Predominant Estrogen: 17 β-estradiol (E2).
Mechanisms in Estrogens:
Estetrol is considered a natural estrogen with unique liver metabolism characteristics.
Ethinyl Estradiol: Primary synthetic estrogen in COCs, features an ethinyl group at C17 to prevent first-pass metabolism.
Enterohepatic Recirculation of Estrogens
Sulfate and Glucuronide conjugations occur in the liver.
Bile secretes these conjugates into the intestine.
Bacterial enzymes later cleave conjugates, allowing reabsorption of active estrogens.
Note: Antibiotics can influence this process and potentially alter efficacy.
IV. Chemistry & Pharmacokinetics of Progestins
Characteristics: C-19 derivatives contain an ethinyl group at C-17, which reduces hepatic metabolism.
Variability in Progestins: Different progestins exhibit diverse androgenic, estrogenic, and anti-estrogenic activities.
Gonane Progestins: (e.g., Norgestimate, Desogestrel) show reduced androgenicity compared to estranes.
Example Product:
Yasmin/Yaz: Combination of Ethinyl Estradiol (30μg) + Drospirenone (3mg); where Drospirenone is a derivative of Spironolactone (anti-androgenic).
V. Mechanism of Action of COCs
Hormonal Effects: High levels of estrogen and progestin result in negative feedback to the hypothalamus, reducing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release.
Follicular Phase: Initiated by a spike in LH in the first half of the menstrual cycle.
Luteal Phase: Corpus luteum releases progesterone leading to a higher P:E ratio.
Consistent Hormonal Levels: With oral contraceptive use, a flat profile of hormones is maintained.
VI. Adverse Effects of COCs
Gastrointestinal Effects:
Nausea and Vomiting: Most commonly reported; advise patient to take with dinner or at bedtime.
Dermatological Effects:
Chloasma: Hyperpigmentation, especially on the face, may occur 1-2 years after starting.
Acne and Hirsutism: Result from increased sebum production due to η≥rogenic activity of progestins.
Cardiovascular Concerns:
Hypertension: Likely to occur 1-3 weeks post initiation; risk is increased with age over 35 and with duration of use.
Thromboembolic Disorders: There is a threefold increased risk, particularly in women taking estrogens. Estrogens increase clotting factors (II, VII, IX, X, XII) and reduce antithrombin III.
Discontinue before major surgery.
Gallbladder and Liver Issues: Risks associated with older high-dose COCs.
Benign Hepatocellular Adenoma: Risk increases after at least four years with an incidence of 3-4 cases per 100,000 users.
VII. Metabolic Effects
Glucose Metabolism: Decreased glucose tolerance, especially in diabetic or pre-diabetic patients.
Lipid Profile Changes: Increased low-density lipoproteins (LDLs) and triglycerides are observed.
Menstrual Changes:
Breakthrough Bleeding (BTB): Most common in the first three months of COC use. Related to hormonal deficiencies that may occur post-ovulation.
Increased risk of infections: Specifically noted for Candida vaginitis.
Central Nervous System: Associated risks of depression and migraines.
Ocular Changes: Some women experience a worsening of myopia or nearsightedness.
Cancer Risks:
Breast Cancer: Slightly increased risk that diminishes after 10 years following cessation.
Cervical Cancer: Increased risk particularly in HPV positive cases plus an approximate 3.4x increased risk for those engaging in COC use longer than five years due to increased sexual activity.
VIII. Fertility & Lactation Effects
Fertility Issues: For women aged 25-29, infertility lasting over 30 months is noted. For those aged 30-34, it may extend up to 72 months.
Lactation Recommendations: COCs should be avoided 3-4 weeks postpartum due to potential impacts on milk quality and quantity.
IX. Beneficial Effects of COCs
Cancer Preventative Benefits:
Endometrial Cancer: Reduces risk by 50-70% after at least 12 months of use; protective for approximately 15 years.
Ovarian Cancer: Decreases risk by 7-9% for each year of use, as progestins prevent endometrial proliferation.
EstroStep®: Variable dosages of Ethinyl Estradiol and Norethindrone acetate.
Yaz®: Indicated for acne treatment for women older than 14 years.
X. Drug-Drug Interactions
Antibiotics Effect: Certain antibiotics may disrupt normal gut flora, interfering with sulfate and glucuronide conjugation of ethinyl estradiol, reducing efficacy due to lack of enterohepatic recirculation.
Anticonvulsants: Some induce liver enzymes (CYP 3A4), which reduces blood levels of ethinyl estradiol, subsequently diminishing contraceptive effectiveness.
Vaginal Ring: Ethinyl estradiol + Etonogestrel; users may report foreign body sensations or emergent removal leading to a requirement for backup contraception if removed for >3 hrs.
Progestin-Only Preparations:
Indicated when estrogen use is contraindicated (for example, in women older than 35 or smokers).
Continuous administration is essential, and a late dose of over 3 hours necessitates backup contraception for 48 hours.
Hormonal effects may not consistently inhibit ovulation (40% cycles may still be ovulatory).
Adverse Effects: Include menstrual irregularities, unpredictable spotting, nausea, and headaches with Norethindrone.
Medroxyprogesterone Preparations
Forms: Administered as an IM injection into gluteal or deltoid muscles every three months, reducing estrogen levels among women but also presenting a risk of bone loss thus increasing osteoporosis risk. Side effects include weight gain.
SQ Self-injection of Medroxyprogesterone: More expensive option.
Nexplanon (Etonogestrel): A subdermal rod implant under the skin.
XI. Emergency Contraception
Plan B®: Consists of one tablet of Levonorgestrel (1.5 mg).
Next Choice: Two tablets of Levonorgestrel (0.75 mg each).
Ella®: Contains Ulipristal acetate (30 mg)—acts as a progesterone antagonist and partial agonist that delays ovulation; should not be used for regular contraception.
Ethinyl Estradiol + Levonorgestrel (Yuzpe regimen): Associated with more side effects than Levonorgestrel alone and is rarely recommended.
Timing for Administration: Must be taken within 120 hours post intercourse, with noted efficacy between 75% - 98% for pregnancy reduction.
Mechanism of Action: Not completely understood but believed to involve delaying or inhibiting ovulation, decreasing endometrial receptivity, and altering gamete transport.
Adverse Effects: Include nausea and vomiting; if these occur within 1-3 hours post ingestion, the dose must be repeated, and antiemetics may be prescribed although this method is not intended for regular use.
Intrauterine Devices (IUDs)
ParaGard (Copper IUD): Functions by preventing fertilization and implantation while reducing sperm viability. It can remain effective for 10 years; associated with low-grade inflammation.
Contraceptive Effectiveness Rates: Approximately 0.8 pregnancies per 100 users for ParaGard and 0.1 pregnancies per 100 users for Mirena, which releases Levonorgestrel. Side effects may include inflammation and the potential for pelvic inflammatory disease (PID) within 20 days of placement in 2.5% of cases, alongside a requirement for proper training for insertion.