Hormonal contraceptives (HCs) contain synthetic analogs of the reproductive hormones estrogen and progesterone. HCs may contain either:
- Progestin + estrogen
- Progestin alone
Choice of contraception
The choice of contraceptive method is very individual and often is dictated by a variety of factors, including:
- Ease of access and use (e.g., dosing regimen, required procedures)
- Efficacy rate
- Reversibility or permanence
- Prevention of STIs
- Adverse effects
- Medical contraindications
Both estrogens and progestins are steroid hormones, making them fat-soluble.
Ethinyl estradiol (EE):
- Very similar in structure to natural estradiol
- Addition of an ethynyl group makes it significantly more stable (i.e., steric hindrance resists metabolic degradation) than estradiol.
- ↑ Bioavailability as compared with estradiol when taken orally
- EE is the only estrogen used in HCs (though dosage varies).
- Similar in structure to natural progesterone
- Addition of a triple bond in most cases makes the molecules more stable.
- Androgenic effects:
- Most are derived from testosterone → have stronger androgenic effects than natural progesterone
- Major exception: drospirenone
- Spironolactone analog
- Has antiandrogenic activity
- Multiple different progestins are used in HCs → different properties of the progestins are responsible for different side-effect profiles of various HCs
Normal physiology of the menstrual cycle
Understanding hormonal regulation of ovulation and the menstrual cycle is key to understanding the mechanisms of HCs. This regulation is primarily by the hypothalamic-pituitary-ovarian (HPO) axis.
- HPO axis:
- Hypothalamus secretes gonadotropin-releasing hormone (GnRH).
- Pituitary secretes:
- Follicle-stimulating hormone (FSH)
- Luteinizing hormone (LH)
- Ovary secretes:
- Follicular/proliferative phase (1st phase of menstrual cycle):
- GnRH pulse stimulates the release of FSH.
- FSH stimulates follicular development within the ovaries.
- Developing follicles produce estrogen, specifically estradiol.
- Stimulates endometrial proliferation
- Inhibits FSH secretion (feedback inhibition)
- Stimulates bone growth
- Triggered by a midcycle surge of LH
- Luteal/secretory phase:
- The ovulated follicle is now called the corpus luteum.
- The corpus luteum produces both estradiol and progesterone.
- Stabilizes endometrium
- Causes endometrium to mature into secretory endometrium, capable of sustaining a pregnancy
- Study tip: progesterone = “progestational hormone” → produced only after ovulation, when gestation is possible
- Estradiol and progesterone are secreted for approximately 14 days after ovulation (time for a fertilized embryo to implant).
- If pregnant: corpus luteum continues producing progesterone until the placenta can take over.
- If not pregnant: corpus luteum involutes → estradiol and progesterone levels fall
- Menstrual phase:
- Loss of stabilizing hormones (particularly progesterone) triggers breakdown of the endometrium → menses
- Key point: Progesterone withdrawal triggers bleeding.
Mechanism of action of hormonal contraceptives
Both estrogens and progestins cause an antiovulatory effect. When used together, this effect is synergistic.
- Estrogen component:
- Inhibits FSH release → prevents the selection and maturation of the dominant follicle = no ovulation
- Would stimulate endometrial proliferation if given alone/without progestins (this is why EE is not given alone)
- Progestin component:
- Inhibits LH surge that is necessary for ovulation
- Effects on the endometrium:
- Natural progesterone is required to make the endometrium healthy for pregnancy; however, the androgenic nature of synthetic progestins thins the endometrial lining, making it unsuitable for implantation.
- All HCs are “progestin-dominant” as compared to estrogen → overall endometrial effect of HCs is endometrial atrophy
- ↑ Cervical mucus viscosity → inhibits sperm transport into the uterus
- ↓ Cilia motility in the fallopian tube
Hormonal contraceptives can be grouped by the length of their action and route of administration. These contraceptives are then classified in different ways, including by their components and dosages.
This category includes pills, patches, rings, and injections. Several common combinations and brand names in each category are given as examples, though there are many different brand names for each.
- Combined oral contraceptive pills (COCP; EE + progestin):
- Daily administration
- Classification by progestin:
- 1st generation (estranes): EE/norethindrone acetate
- 2nd generation (gonanes): EE/norgestrel, EE/levonorgestrel
- 3rd generation: EE/desogestrel, EE/norgestimate
- 4th generation/unclassified: EE/drospirenone (e.g., Yaz®)
- Classification by number of “phases”:
- Monophasic: Each pill in the pack contains the same amount of hormone.
- Triphasic: The amount of hormone varies from pill to pill in the pack.
- Many different EE/progestin combinations can come in both monophasic and triphasic packs.
- Progestin-only pills (POPs):
- Daily administration
- Hormones: norethindrone acetate
- Transdermal patch:
- Weekly administration (i.e., 1 patch applied per week)
- Hormones: EE/norelgestromin
- Vaginal ring:
- “Monthly” administration (i.e., 1 ring inserted for 3 weeks)
- Hormones: EE/etonorgestrel (e.g., NuvaRing®)
- Progestin contraceptive injections:
- “Quarterly” administration (i.e., 1 injection every 3 months)
- Hormones: depot medroxyprogesterone acetate (DMPA, e.g., Depo-Provera®)
Long-acting reversible contraceptives (LARCs)
- Subdermal contraceptive implants (etonogestrel implant):
- Nexplanon®: lasts 3 years
- Intrauterine device (IUDs): levonorgestrel IUDs
- Mirena®, Liletta® (52 mg of levonorgestrel): last 5–7 years
- Kyleena® (19.5 mg of levonorgestrel): lasts 5 years
- Skyla® (13.5 mg of levonorgestrel): lasts 3 years
Refers to contraception administered after unprotected intercourse (UPI; called “the morning after pill”). These options act to prevent fertilization and/or implantation and are not used as postimplantation abortifacients.
- Insertion of an IUD:
- More effective than oral methods
- Provide ongoing contraception
- Not impacted by BMI or risk of pregnancy (e.g., UPI midcycle, multiple episodes of UPI)
- Copper IUD (Paragard®)
- Levonorgestrel 52-mg IUD
- Oral methods:
- Less effective in individuals with BMI > 30
- Less effective in individuals at higher risk of pregnancy
- Ulipristal acetate (can be used up to 5 days after UPI)
- Oral levonorgestrel (can be used up to 3 days after UPI)
Methods of administration
- Hormone-free interval:
- Pills/patches/rings containing hormones are typically used for 21–24 days in a row (ovulation and endometrial growth are suppressed during this time).
- This is followed by a hormone-free interval (HFI):
- Typically 4–7 days in length
- Pill packs include placebo pills during the HFI; the patch/ring is withheld during this time.
- Withdrawal of the progestin triggers a withdrawal bleed (similar to menses), which is why skipping pills can lead to irregular bleeding.
- Cyclic administration:
- Hormones taken for 21–24 days followed by 4–7-day HFI
- Results in monthly withdrawal bleeding
- Prolonged cyclic administration:
- Hormones taken for up to 84 days (12 weeks) followed by a 4–7-day HFI
- Results in withdrawal bleeding only during the HFIs (typically 4 times per year)
- Some brands are designed this way, though any monophasic pill, the patch, and the ring can be used this way.
- Hormone use can be extended beyond 12 weeks if tolerated by the patient.
- Continuous administration:
- Hormones are taken continuously, with no HFI.
- Monophasic pills, the patch, and vaginal ring can all be administered this way.
- Completely suppresses menstruation and symptoms associated with hormone fluctuations (e.g., menstrual migraines)
- Higher risk of breakthrough bleeding owing to prolonged endometrial atrophy
- Emergency contraception:
- Taken as a single course as soon as possible after UPI
- Specific regimens depend on days from UPI and medications/methods chosen.
- Rapid absorption via any route (e.g., oral, topical, and vaginal)
- Oral bioavailability: approximately 50% (estradiol is only approximately 5%)
- Highly protein-bound: approximately 98% (primarily albumin; unlike estradiol, EE does not bind well to sex hormone–binding globulin (SHBG))
- Steroid hormones → distributed throughout the body
- High 1st-pass metabolism (though significantly less than for estradiol)
- Conjugated via glucuronidation and sulfation to inactive metabolites
- Also hydroxylated via CYP3A4
- Enterohepatic recirculation occurs
- Oral half-life: approximately 10–16 hours
- Fecal: 60%
- Urine: 40%
- High oral bioavailability
- IUD components have low (but some) systemic absorption.
- LARCs secrete decreasing amounts of progestins daily the longer they are in place.
- Highly protein-bound
- Some bind more to albumin; others bind more to SHBG.
- Most undergo 1st-pass hepatic metabolism to inactive metabolites.
- Some are metabolized by the CYP450 system.
- Enterohepatic recirculation can occur.
- In both urine and feces
- Oral half-life: approximately 20–40 hours
- Abnormal uterine bleeding (e.g., heavy, prolonged, or frequent bleeding)
- Good options:
- Levonorgestrel IUDs
- Generally avoided owing to higher risks of abnormal bleeding:
- Etonorgestrel implant
- Good options:
- Dysmenorrhea and/or endometriosis
- Polycystic ovarian syndrome
- Premature ovarian insufficiency (i.e., premature menopause)
- Other specific indications:
- Menstrual symptoms (especially menstrual migraines and premenstrual syndrome (PMS)): continuous COCPs/patch/ring
- Hirsutism: COCPs containing the antiandrogenic progestin drospirenone
- Endometrial hyperplasia: levonorgestrel 52-mg IUDs
Adverse Effects and Contraindications
Most of the adverse effects can be seen with either EE or progestins and are possible with any of the HC methods.
- Risk of venous thromboembolism (VTE):
- Significantly greater risk with EE than with progestins
- Ethinyl estradiol should be avoided in people at risk for VTE; progestin-only methods are recommended for these individuals.
- Note: Most progestins list VTE as a potential risk/contraindication as well, though large studies suggest that there is no significantly increased risk in progestin-only contraceptive users.
- Abnormal bleeding (e.g., unscheduled bleeding, prolonged bleeding)
- Estrogen tends to stabilize bleeding patterns, so this is more often associated with progestin-only methods
- Worst with etonogestrel implant
- Mood changes
- Decreased libido
- Altered lipid metabolism and insulin effects
- Breast symptoms:
- Fibrocystic breast changes
- Mastalgia (breast pain), especially cyclic
- Decreased breast milk production during breastfeeding (EE only)
- Ovarian cysts (progestin-only methods, since EE generally suppresses cyst formation)
- Unique adverse effects:
- Vaginal ring: ↑ vaginal discharge
- DMPA injections: bone loss (reversible)
- Implant: high association with irregular bleeding as compared with other methods
- Pelvic pain
- Uterine perforation
- If pregnancy occurs, significantly ↑ risk of that pregnancy being ectopic (though the absolute rate of ectopic pregnancy is lower in IUD users than in individuals on no contraception)
Drug interactions of combined oral contraceptive pills and progestin-only pills
The metabolism of COCP and POPs is increased by any drugs that increase liver microsomal enzyme activity, resulting in reduced contraceptive efficacy. These drugs include:
- Lamotrigine (HC retains efficacy but concentrations of lamotrigine are ↓ )
- The vast majority of antibiotics do not interact with HCs.
- Antiretroviral drugs
- Nonnucleoside reverse transcriptase inhibitors (e.g., efavirenz)
- Protease inhibitors (e.g., ritonavir)
The “Summary Chart of U.S. Medical Eligibility Criteria for Contraceptive Use” by the Centers for Disease Control and Prevention (CDC) notes the specific risks of each contraceptive method and > 100 different conditions. This document is a critical resource when determining the safety of a particular method for a specific individual. The most important contraindications are noted below.
EE-containing HCs (COCPs/patch/ring):
- Current, history of, or risk factors for, VTE, including:
- < 21 days postpartum
- Smoking in women > 35 years
- Certain coagulopathies
- Systemic lupus erythematosus (SLE)
- Cardiovascular disease:
- Ischemic heart disease
- Peripartum cardiomyopathy
- Valvular heart disorders with complications
- Migraines with aura
- Undiagnosed abnormal uterine bleeding (AUB)
- Current or past breast cancer
- Liver disease, including:
- Decompensated liver cirrhosis
- Hepatocellular adenoma
- Liver cancer
- Diabetes > 20 years or with vascular disease (neuropathy, nephropathy, retinopathy)
- Solid-organ transplantation with complications
Generally preferred methods in patients at risk for VTE. Beyond that, contraindications are similar to EE-containing HCs and include:
- Current or past breast cancer
- Undiagnosed AUB
- Liver disease
- Additional contraindications specific to IUDs:
- Uterine anomalies
- Pelvic inflammatory disease (PID) or endometritis
Acute cervicitis or vaginitis (e.g., Chlamydia trachomatis or bacterial vaginosis infections at the time of planned IUD insertion)
Comparison of Different Contraceptive Methods
|Method||Major downsides||Reasons to pick this method|
||Same reasons as COCPs, but:
||Same reasons as COCPs, but:
- Allen, R. H. (2021). Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use. UpToDate. Retrieved August 2, 2021, from https://www.uptodate.com/contents/combined-estrogen-progestin-oral-contraceptives-patient-selection-counseling-and-use
- Roe, A., et al. (2021). Combined estrogen-progestin oral contraceptives: Side effects and health concerns. UpToDate. Retrieved August 2, 2021, from https://www.uptodate.com/contents/combined-estrogen-progestin-contraception-side-effects-and-health-concerns
- Kaunitz, A. M. (2021). Progestins-only pills (POPs) for contraception. UpToDate. Retrieved August 2, 2021, from https://www.uptodate.com/contents/progestin-only-pills-pops-for-contraception
- Kaunitz, A. M. (2021). Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits. UpToDate. Retrieved August 3, 2021, from https://www.uptodate.com/contents/depot-medroxyprogesterone-acetate-dmpa-efficacy-side-effects-metabolic-impact-and-benefits
- Kaunitz, A. M. (2021). Depot medroxyprogesterone acetate (DMPA): formulations, patient selection, and drug administration. UpToDate. Retrieved August 3, 2021, from https://www.uptodate.com/contents/depot-medroxyprogesterone-acetate-dmpa-formulations-patient-selection-and-drug-administration
- Darney, P. D. (2021). Etonogestrel contraceptive implant. UpToDate. Retrieved August 3, 2021, from https://www.uptodate.com/contents/etonogestrel-contraceptive-implant
- Casey, F. E. (2020). Oral contraceptives. MSD Manual Professional Version. Retrieved August 4, 2021, from https://www.msdmanuals.com/professional/gynecology-and-obstetrics/family-planning/oral-contraceptives
- Casey, F. E. (2020). Progestin contraceptive injections. MSD Manual Professional Version. Retrieved August 4, 2021, from https://www.msdmanuals.com/professional/gynecology-and-obstetrics/family-planning/progestin-contraceptive-injections
- Casey, F. E. (2020). Subdermal contraceptive implants. MSD Manual Professional Version. Retrieved August 4, 2021, from https://www.msdmanuals.com/professional/gynecology-and-obstetrics/family-planning/subdermal-contraceptive-implants
- Casey, F. E. (2020). Intrauterine devices (IUDs; IUD). MSD Manual Professional Version. Retrieved August 3, 2021, from https://www.msdmanuals.com/professional/gynecology-and-obstetrics/family-planning/intrauterine-device-iuds-iud
- Centers for Disease Control and Prevention (2016). Summary Chart of U.S. Medical Eligibility Criteria for Contraceptive Use. Retrieved Oct 5, 2021, from https://www.cdc.gov/reproductivehealth/contraception/pdf/summary-chart-english-bw-508-tagged.pdf