Hormonal Contraception — GOND Module 2

Gonadal Pharmacology · Module 2 of 5

Hormonal Contraception

Combined oral contraceptives work through a hierarchy of three mechanisms — anovulation is the dominant effect in over 99% of cycles, achieved by sustained estrogen and progestin suppression of the hypothalamic-pituitary-ovarian axis preventing the LH surge; cervical mucus thickening acts as a secondary barrier; and endometrial atrophy operates only as a tertiary backup if the first two mechanisms fail.
Progestin-only methods differ from each other in mechanism and clinical demands: the norethindrone minipill acts almost entirely through cervical mucus thickening with a rigid 3-hour dosing window; the desogestrel minipill additionally suppresses ovulation and has a 12-hour window; long-acting methods (etonogestrel implant, depot medroxyprogesterone acetate, levonorgestrel IUD) suppress ovulation systemically or act locally, removing the daily compliance burden entirely.
Emergency contraception efficacy depends critically on timing relative to ovulation: levonorgestrel 1.5 mg is effective only pre-ovulatorily (up to 72 hours), shows reduced efficacy above BMI 26 kg/m², and fails entirely post-ovulation; ulipristal acetate 30 mg can delay ovulation even after the LH surge has begun (effective up to 120 hours); the copper IUD is the most effective option at any time point and has no weight or hormonal interaction limitations.
The WHO Medical Eligibility Criteria distinguish between combined hormonal methods (containing ethinyl estradiol) and progestin-only methods for contraindication purposes — most Category 3–4 conditions for combined methods (VTE history, migraine with aura, hypertension, smoking over age 35, liver disease) are Category 1–2 for progestin-only methods, because the risk derives from the estrogen component, not from progestin itself.
The single major exception to the progestin-only safety advantage is current active breast cancer — both combined and progestin-only hormonal methods are WHO MEC Category 4 (absolute contraindication) for active breast cancer, because progesterone receptors are expressed on breast cancer cells and progestin exposure may drive tumor proliferation.

Combined Oral Contraceptive — Mechanism Hierarchy

Primary — 99%+ of Cycles

Anovulation

Sustained estrogen + progestin suppresses the hypothalamic-pituitary-ovarian axis
No LH surge → no ovulation → no egg to fertilize
Disrupted by missed pills, vomiting within 2 hours, enzyme-inducing drugs

Secondary

Cervical Mucus Thickening

Progestin converts cervical mucus to viscous, impermeable state
Blocks sperm penetration and transport
Primary mechanism of norethindrone minipill (no anovulation at 0.35 mg)
Norethindrone: strict 3-hour dosing window — permeability returns by hour 4

Tertiary Backup Only

Endometrial Atrophy

Thin, poorly vascularized endometrium unsuitable for implantation
Operates only if mechanisms 1 and 2 have both failed
Not a primary contraceptive mechanism in any method
Explains lighter or absent withdrawal bleeds on hormonal methods

Progestin-Only Methods Compared

Method	Primary Mechanism	Duration	Key Advantage	Key Counseling Point
Norethindrone minipill 0.35 mg	Cervical mucus thickening	Daily — 3-hr window	No estrogen; usable in VTE, migraines with aura	Strictest timing of all hormonal methods — missed by 3 hours = unprotected
Desogestrel minipill 75 mcg	Ovulation suppression + mucus thickening	Daily — 12-hr window	Ovulation suppression without estrogen	More forgiving than norethindrone; preferred minipill where available
Etonogestrel implant (Nexplanon)	Ovulation suppression	3 years	Most effective reversible contraceptive (<0.1% failure)	Irregular bleeding common in year 1; fertility returns within 3–4 weeks of removal
Depot MPA (DMPA)	Ovulation suppression	12 weeks per injection	Large depot — robust against missed doses and interactions	Fertility delay: average 9–10 months after last injection — counsel before starting
LNG-IUD 52 mg	Local endometrial + mucus thickening	5–8 years	Minimal systemic exposure; no systemic drug interactions	Preferred when on enzyme-inducing drugs (rifampin, EIAEDs) — local action unaffected

Emergency Contraception — Options and Hierarchy

Up to 72 Hours

Levonorgestrel 1.5 mg

Inhibits or delays LH surge — effective pre-ovulatorily only
No effect if ovulation has already occurred
Efficacy reduced at BMI >26 kg/m²; substantially impaired at BMI >35
Over-the-counter availability; no prescription required
Offer ulipristal or copper IUD if patient is above BMI threshold

Up to 120 Hours (5 Days)

Ulipristal Acetate 30 mg

Selective progesterone receptor modulator — delays follicular rupture
Can inhibit ovulation even after the LH surge has begun (unique advantage)
Superior to levonorgestrel at all time points; especially after 72 hours
Less weight-dependent than levonorgestrel
Avoid within 5 days of progestin-containing contraception — pharmacological antagonism

Most Effective — Up to 5 Days

Copper Intrauterine Device

Copper ions toxic to sperm → prevents fertilization before and after ovulation
Failure rate <0.1% — most effective emergency contraceptive available
Not weight-dependent; no hormonal interactions
Provides ongoing contraception for up to 10 years
Preferred backup when patient is on any hormonal method or enzyme-inducing drug

WHO MEC — Combined vs. Progestin-Only Contraindications

Condition	Combined Hormonal	Progestin-Only	Rationale
Prior VTE or thrombophilia	Category 4 — absolute CI	Category 2 — safe	EE amplifies hepatic coagulation factor production; progestin-only does not
Migraine with aura	Category 4 — absolute CI	Category 2 — safe	EE multiplies ischemic stroke risk; progestin-only does not share this signal
Severe / uncontrolled hypertension	Category 4 — absolute CI	Category 2–3	Controlled hypertension: Category 3 for combined, Category 1–2 for progestin-only
Age >35 and heavy smoking	Category 4 — absolute CI	Category 2 — safe	Synergistic arterial thrombotic risk with EE; progestin-only avoids this
Active liver disease	Category 4 — absolute CI	Category 3	EE is metabolized by and stimulates a compromised liver; progestin-only: relative CI only
Current active breast cancer	Category 4 — absolute CI	Category 4 — absolute CI	Exception to the rule — ALL hormonal methods contraindicated; progesterone receptors drive tumor growth

Core Rule — Progestin-Only Safety Advantage and Its One Exception

Most conditions that make combined hormonal contraception WHO MEC Category 3 or 4 are Category 1 or 2 for progestin-only methods — because the risk arises from ethinyl estradiol, not from progestin. This includes VTE history, migraine with aura, uncontrolled hypertension, smoking over age 35, and active liver disease. Progestin-only methods are the appropriate choice in all of these situations.

The single exception is current active breast cancer: Category 4 for both combined and progestin-only methods. Breast cancer cells frequently express progesterone receptors, and progestin exposure is contraindicated regardless of estrogen content. In this setting, only non-hormonal contraception (copper IUD, barrier methods) is appropriate.

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter 40: Estrogens, Progestins, and the Female Reproductive Tract	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed. — Chapter 44: Estrogens and Progestins	McGraw-Hill; 2023
Hatcher RA, Nelson AL, Trussell J, et al.	Contraceptive Technology, 21st ed.	Ayer Company Publishers; 2018
McCann MF, Potter LS.	Progestin-only oral contraception: a comprehensive review	Contraception. 1994;50(6 Suppl 1):S1–195
Trussell J.	Contraceptive failure in the United States	Contraception. 2011;83(5):397–404
Schindler AE.	Non-contraceptive benefits of oral hormonal contraceptives	Int J Endocrinol Metab. 2013;11(1):41–47
Lidegaard O, Nielsen LH, Skovlund CW, et al.	Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses	BMJ. 2011;343:d6423
World Health Organization.	Medical Eligibility Criteria for Contraceptive Use, 5th ed.	WHO Press; 2015
Mansour D, Inki P, Gemzell-Danielsson K.	Efficacy of contraceptive methods: a review of the literature	Eur J Contracept Reprod Health Care. 2010;15(1):4–16
Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T.	Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD	Clin Endocrinol (Oxf). 1982;17(5):529–536
Glasier AF, Cameron ST, Fine PM, et al.	Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis	Lancet. 2010;375(9714):555–562
Brache V, Cochon L, Deniaud M, Croxatto HB.	Ulipristal acetate prevents ovulation more effectively than levonorgestrel: analysis of pooled data from three randomized trials	Contraception. 2013;88(5):611–618
Simmons KB, Haddad LB, Nanda K, Curtis KM.	Drug interactions between rifamycin antibiotics and hormonal contraception: a systematic review	BJOG. 2018;125(7):804–811
Reimers A, Brodtkorb E, Sabers A.	Interactions between hormonal contraception and antiepileptic drugs: clinical and mechanistic considerations	Seizure. 2015;28:66–70
Lidegaard O, Lokkegaard E, Jensen A, et al.	Thrombotic stroke and myocardial infarction with hormonal contraception	N Engl J Med. 2012;366(24):2257–2266