Residency · Residency · Obstetrics Gynecology

Hormonal Contraception: Combined and Progestin-Only Methods

Introduction

Short-acting hormonal contraceptives remain the most widely used reversible methods worldwide. These include combined hormonal contraceptives (CHCs) containing both estrogen and progestin, and progestin-only methods. Understanding formulation differences, mechanisms, eligibility criteria, and side effect management is essential for effective contraceptive counseling in clinical practice.

Combined Hormonal Contraceptives

Formulations and Delivery Systems

Combined oral contraceptives (COCs) are available in monophasic, biphasic, triphasic, and quadriphasic formulations, with most containing ethinyl estradiol at 20 to 35 mcg combined with a progestin. The contraceptive patch (Xulane) delivers norelgestromin and ethinyl estradiol transdermally, applied weekly for 3 weeks with 1 patch-free week, and produces higher overall ethinyl estradiol exposure than oral formulations. The vaginal ring (NuvaRing) releases etonogestrel and ethinyl estradiol, worn continuously for 3 weeks and removed for 1 week. The segesterone acetate/ethinyl estradiol ring (Annovera) is reusable for 13 cycles. Estrogen types include ethinyl estradiol (the most common), estradiol valerate (in Natazia), and estetrol (in Nextstellis), with newer estrogen formulations potentially carrying lower venous thromboembolism risk.

Progestin Generations and Androgenic Profiles

First-generation progestins include norethindrone and norethindrone acetate, which have moderate androgenic activity. Second-generation progestins such as levonorgestrel and norgestrel have higher androgenic activity but carry the lowest VTE risk among COCs. Third-generation progestins including desogestrel, norgestimate, and gestodene have lower androgenicity but a slightly higher VTE risk. Fourth-generation progestins, specifically drospirenone, have anti-androgenic and anti-mineralocorticoid properties with approximately 25 mg spironolactone-equivalent activity. Potassium should be monitored in patients taking drospirenone-containing COCs concurrently with ACE inhibitors or potassium-sparing diuretics.

Mechanism of Action

The primary mechanism is ovulation suppression via inhibition of the midcycle LH and FSH surge. Secondary mechanisms include cervical mucus thickening, which reduces sperm penetration, and endometrial atrophy, which creates an unfavorable environment for implantation. The typical-use failure rate is 7 to 9% per year, primarily due to inconsistent use rather than method failure.

<image>Diagram illustrating the mechanism of combined hormonal contraception showing the hypothalamic-pituitary-ovarian axis with estrogen and progestin suppression of GnRH pulsatility, LH/FSH surge inhibition, and peripheral effects on cervical mucus and endometrium</image>

Medical Eligibility Criteria (US MEC)

Category 4 conditions, where the risk is unacceptable, include history of venous thromboembolism or pulmonary embolism, known thrombogenic mutations (Factor V Leiden, prothrombin mutation), current or history of breast cancer, migraine with aura at any age, smoking 15 or more cigarettes per day in women 35 years or older, uncontrolled hypertension (160/100 or greater), ischemic heart disease, stroke, complicated valvular disease, and hepatocellular adenoma or hepatoma. Category 3 conditions, where risks generally outweigh benefits, include smoking fewer than 15 cigarettes per day in women 35 or older, adequately controlled hypertension, history of breast cancer with no recurrence for 5 years, migraine without aura in women 35 or older, and peripartum cardiomyopathy with normal cardiac function. Category 1, with no restriction, applies to nulliparity, history of ectopic pregnancy, varicose veins, uterine fibroids, and endometriosis, while obesity with a BMI of 30 or greater is Category 2. Important drug interactions include CYP3A4 inducers (rifampin, phenytoin, carbamazepine, phenobarbital), which significantly reduce efficacy. Lamotrigine levels are reduced by COCs, which can precipitate seizures.

Non-Contraceptive Benefits

COCs provide menstrual regulation and reduction of dysmenorrhea and menorrhagia. Ovarian cancer risk is reduced by 40 to 50% with 5 or more years of use, with the protective effect persisting for 15 to 20 years after discontinuation. Endometrial cancer risk is reduced by 50% with 4 or more years of use. Acne and hirsutism improve, particularly with anti-androgenic progestins such as drospirenone. Endometriosis symptoms are managed effectively with continuous or extended cycling.

Risks and Side Effects

Venous thromboembolism risk is increased 3 to 4 fold over baseline. The baseline risk is 1 to 5 per 10,000 woman-years, and with COC use this rises to 3 to 9 per 10,000. Risk is highest in the first year of use and with higher ethinyl estradiol doses. Arterial events including myocardial infarction and stroke are increased in women with additional risk factors such as smoking, hypertension, or migraine with aura. Breakthrough bleeding is common in the first 3 cycles and should prompt reassurance and continuation; persistent breakthrough bleeding warrants evaluation for cervical pathology, STIs, or nonadherence. Breast cancer risk is slightly increased with a relative risk of 1.2, but this diminishes after discontinuation.

Progestin-Only Methods

Progestin-Only Pills (POPs)

Traditional POPs containing norethindrone 0.35 mg must be taken within the same 3-hour window daily. Their mechanism is primarily cervical mucus thickening with partial ovulation suppression. The drospirenone POP (Slynd) contains 4 mg drospirenone in a 24/4 regimen and allows a 24-hour missed pill window, which is a significant practical advantage. It more reliably suppresses ovulation than traditional POPs. The typical-use failure rate is 7 to 9% for traditional POPs and likely lower for the drospirenone formulation. POPs are safe for women with contraindications to estrogen including migraine with aura, history of VTE, hypertension, and during lactation.

Depot Medroxyprogesterone Acetate (DMPA)

DMPA-IM (Depo-Provera) is administered as a 150 mg intramuscular injection every 11 to 13 weeks. DMPA-SC (Depo-SubQ Provera 104) is a 104 mg subcutaneous injection that can be self-administered. The mechanism is reliable ovulation suppression along with cervical mucus thickening and endometrial atrophy. The typical-use failure rate is 4 to 6%. Side effects include irregular bleeding progressing to amenorrhea (50% at 1 year), weight gain averaging 5 to 8 pounds over 2 years, and delayed return to fertility with a median of 10 months after the last injection. Bone mineral density decreases reversibly by 5 to 7% over 2 years. The FDA black box warning limits use to 2 years unless alternatives are inadequate, though ACOG states that the benefits generally outweigh the risks and the 2-year limit should not be applied rigidly, especially in adolescents.

<image>Comparison chart of short-acting hormonal contraceptive methods showing COCs, patch, ring, progestin-only pills, and DMPA injection with typical-use failure rates, dosing schedules, advantages, disadvantages, and key contraindications for each method</image>

Extended and Continuous Cycling

Extended cycling uses 84 active pills followed by 7 placebo days, as in Seasonale and Seasonique, resulting in only 4 withdrawal bleeds per year. Continuous use involves skipping all placebo pills entirely to achieve amenorrhea and is safe and effective with any monophasic COC. Benefits include reduced menstrual-related symptoms, fewer headaches during hormone-free intervals, and improved quality of life for patients with endometriosis or menstrual migraine. Breakthrough bleeding during continuous use can be managed with a 3 to 4 day hormone-free interval to reset the endometrium.

Initiating Contraception

The Quick Start method, which is preferred, allows hormonal contraception to begin on the day of the visit regardless of cycle day after reasonably excluding pregnancy, with backup contraception used for 7 days. The Sunday Start begins on the first Sunday after menses onset. The First Day Start begins on the first day of menstrual bleeding and requires no backup method. Bridging involves providing a short-acting method while awaiting LARC placement. In the postpartum period, CHCs should be avoided in the first 21 days due to VTE risk, while POPs and DMPA can be started immediately.

<image>Clinical decision flowchart for selecting appropriate hormonal contraception based on patient history including VTE risk factors, migraine type, blood pressure, BMI, breastfeeding status, and medication interactions</image>

Clinical Pearls

Migraine with aura is an absolute contraindication to all estrogen-containing contraceptives (US MEC Category 4) due to stroke risk. Progestin-only methods are safe alternatives.

Quick Start is the preferred initiation method to reduce barriers and improve contraceptive uptake. Waiting for menses to begin is unnecessary.

DMPA-associated bone loss is reversible after discontinuation. Prolonged use is acceptable when benefits outweigh risks, and the FDA 2-year limit should not be applied rigidly.

The drospirenone POP (Slynd) offers a wider missed-pill window and more reliable ovulation suppression than traditional norethindrone POPs, making it a significantly more forgiving option for patients who struggle with strict timing.

All hormonal contraceptives can be used continuously to achieve therapeutic amenorrhea when clinically indicated, such as for endometriosis, menstrual migraine, or patient preference.

References

1. Curtis KM, Jatlaoui TC, Tepper NK, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep. 2016;65(3):1-103.
2. ACOG Practice Bulletin No. 206. Use of Hormonal Contraception in Women with Coexisting Medical Conditions. Obstet Gynecol. 2019;133(2):e128-e150.
3. Collaborative Group on Hormonal Factors in Breast Cancer. Hormonal contraception and the risk of breast cancer. Lancet. 2017;390(10113):e35.
4. Lopez LM, Grimes DA, Schulz KF. Steroidal contraceptives: effect on bone fractures in women. Cochrane Database Syst Rev. 2014;(6):CD006033.

Read this lecture as Markdown