5.2 Hormonal Contraceptives: Combined & Progestin-Only Methods

Mechanisms of Combined Hormonal Contraceptives (CHCs)

Combined hormonal contraceptives (CHCs)—oral pills, transdermal patches, and vaginal rings—contain an estrogen and a progestin component that act synergistically to inhibit conception via negative feedback on the hypothalamic-pituitary-ovarian (HPO) axis:

1. Estrogen Component (FSH Suppression): Suppresses pituitary secretion of follicle-stimulating hormone (FSH), preventing dominant ovarian follicle recruitment and selection. Estrogen also stabilizes the endometrial vascular architecture to minimize unscheduled breakthrough bleeding.
2. Progestin Component (LH Suppression & Peripheral Hostility): Suppresses the mid-cycle luteinizing hormone (LH) surge from the anterior pituitary, reliably inhibiting ovulation. Progestins also induce peripheral contraceptive barriers: thickening cervical mucus within hours into a viscid, sperm-impenetrable plug, altering fallopian tubal ciliary transit, and inducing endometrial stromal decidualization and glandular atrophy hostile to blastocyst implantation.

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Estrogen Formulations & Progestin Generations

Estrogen Components

• Ethinyl Estradiol (EE): Synthetic 17α-alkylated estradiol resistant to hepatic first-pass metabolism, with modern low-dose formulations containing 10–35 mcg. Doses ≥50 mcg are obsolete for routine contraception due to venous thromboembolism (VTE) risks.
• Estradiol Valerate: Synthetic ester prodrug rapidly cleaved to 17β-estradiol, matched with dienogest in a four-phase oral regimen.
• Estetrol (E4): Native estrogen produced by the human fetal liver during pregnancy. Characterized as a Native Estrogen with Selective tissue activity (NEST), E4 displays agonistic activity on bone, endometrium, and vagina, but neutral-to-antagonistic activity on breast tissue and hepatic hemostasis. Formulated with drospirenone (14.2 mg E4 / 3 mg DRSP), it exerts minimal impact on coagulation factors and lipids compared to EE.

Progestin Generations & Receptor Profiles

Progestins bind to progesterone receptors (PR) but exhibit cross-reactivity with androgen (AR) and mineralocorticoid (MR) receptors:

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Non-Oral Combined Delivery Systems

Transdermal Contraceptive Patch

• Formulation: Norelgestromin 150 mcg / ethinyl estradiol 35 mcg daily (Xulane, Zafemy) applied weekly for 3 consecutive weeks followed by 1 patch-free week; levonorgestrel / EE patch (Twirla).
• Pharmacokinetics: Bypasses hepatic first-pass metabolism, providing continuous steady-state hormone levels. However, total systemic estrogen exposure (AUC) is up to 60% higher than standard 35 mcg oral COCs.
• Weight & BMI Warning: Current Xulane labeling carries a boxed warning that the patch is contraindicated with BMI ≥30 kg/m² (higher VTE risk) and in smokers over 35; the label also notes it may be less effective at ≥90 kg (198 lb). The levonorgestrel patch (Twirla) is likewise contraindicated at BMI ≥30.
• Application: Apply to clean, dry skin on the buttocks, abdomen, upper arm, or torso. Application to the breasts is strictly contraindicated.

Contraceptive Vaginal Rings

• Etonogestrel / EE Ring (NuvaRing, EluRyng): Releases 120 mcg etonogestrel / 15 mcg EE daily. Inserted for 3 weeks (21 days), followed by 1 ring-free week (7 days). If the ring has been out for 48 hours or longer, reinsert it and use backup contraception for 7 days; if out less than 48 hours, reinsert as soon as possible with no backup (US SPR 2024).
• Segesterone Acetate / EE Ring (Annovera): Reusable silicone elastomer ring releasing 150 mcg segesterone / 13 mcg EE daily. Kept in place for 21 days, removed for 7 days (washed and stored in its case), and reinserted for a total of 13 cycles (1 full year).

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Progestin-Only Pills (POPs)

• Traditional Norethindrone POP (0.35 mg): Taken daily without hormone-free intervals. Primary mechanism is cervical mucus thickening (peaks at 4 hours, wanes by 20–24 hours) and endometrial thinning; ovulation is inhibited in only ~50% of cycles. Due to this pharmacokinetics, taking a pill >3 hours late constitutes a missed dose. If late by >3 hours, take the pill immediately, resume the daily schedule, and use backup barrier contraception for 48 hours.
• Norgestrel POP (Opill, 0.075 mg): Approved for over-the-counter sale in 2023; like norethindrone, it has a 3-hour window and acts mainly by thickening cervical mucus.
• Drospirenone POP (Slynd, 4 mg 24/4 regimen): Deeply suppresses pituitary ovulation and thickens cervical mucus. Provides a 24-hour missed-pill window, offering the forgiveness of COCs without estrogenic thromboembolic risks.

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Depot Medroxyprogesterone Acetate (DMPA)

Administered as 150 mg IM (deltoid or gluteal) or 104 mg SubQ (anterior thigh or abdomen) every 13 weeks. A 2-week grace period (up to 15 weeks) applies before pregnancy exclusion is needed.

• Endocrine Effects & Bleeding: Suppresses hypothalamic GnRH pulsatility and pituitary FSH/LH secretion, abolishing ovulation. Initial unscheduled spotting resolves into amenorrhea in 50% of users at 1 year and 70% at 2 years.
• Bone Mineral Density (BMD) Counseling: Hypoestrogenism causes reversible bone density reduction, most pronounced during years 1–2. The FDA Black Box warning recommends limiting use to 2 years unless other methods are inadequate; however, ACOG, CDC, and WHO consensus guidelines advise against arbitrarily restricting duration to 2 years, as bone density recovers post-discontinuation and fracture risk is not elevated. Counsel on 1,000–1,200 mg daily elemental calcium, 600–800 IU vitamin D, and weight-bearing exercise. Routine DEXA scans are not recommended.
• Delayed Fertility Return: Median time to ovulation following discontinuation is 9 to 10 months, extending up to 18 months.