Combined hormonal contraceptives (CHCs) containing both estrogen and progestin are common go-to agents for contraception. However, on occasion, CHCs are an inappropriate choice given the multiple contraindications of estrogen. Approximately 20% of women using contraception are using progestin-only products, including progestin-only pills (POPs;  also known as the “mini-pill”), depot-medroxyprogesterone acetate injection, subdermal etonogestrel implants, and levonorgestrel intrauterine devices (IUD). Progestin-only products are an alternative option for females who cannot or prefer not to use estrogen-containing contraceptives. Below we provide a comparison table of progestin-only products.

As a brief reminder (and as a great review for anyone taking a board exam!), some of the contraindications for CHCs include the following: 

• Age ≥35 years and smoking ≥15 cigarettes/day
• Multiple risk factors for ASCVD (i.e., older age, smoking, diabetes, hypertension)
• Hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg)
• Venous thromboembolism (unless on anticoagulation)
• Known ischemic heart disease
• History of stroke
• Current breast cancer
• Migraine with aura
• Postpartum (absolute <21 days, up to 42 days if other risk factors for VTE)

Multiple types of progestins are used in CHCs, however, the most common progestins in POPs are norethindrone or drospirenone. A general consensus has been created in the medical community that POPs are inferior to CHCs. This primarily results from the fact that norethindrone as the sole progestin does not consistently suppress ovulation. Approximately 50% of users using this contraceptive method still ovulate, however, the failure rate is reduced to only about 5% of users due to its other mechanisms to prevent conception. This includes thickening of the cervical mucus to prevent sperm migration, thinning the endometrium, and slowing down egg travel through fallopian tubes. Drospirenone was only recently FDA-approved (2019) and DOES suppress ovulation, unlike norethindrone. Although head-to-head comparison studies have yet to be produced, this mechanism causes experts to believe drospirenone POPs may be more effective than norethindrone-based products. 

Drospirenone additionally comes with anti-androgen activity, meaning less of a risk for common androgenic effects such as acne, hair growth, and weight gain. Drospirenone also provides more flexibility with adherence, as a norethindrone missed dose of just >3 hours may require backup contraception. Norethindrone POPs include 28 days of active pills with no placebo pills, which has led to inconsistent menstrual bleeding and intermittent amenorrhea commonly occurring in users. This has not been linked with drospirenone products, perhaps due to the scheduled 4 placebo pills (after 24 active pills). Both of these POPs are most commonly seen in breastfeeding women. A few contraindications for progestin-only products include:

• Known or suspected pregnancy
• Known or suspected breast cancer
• Undiagnosed abnormal uterine bleeding
• Benign or malignant liver tumors, severe cirrhosis, or acute liver disease

Some of the most common emergency contraceptives (i.e. Plan B) are progestin-only. If taken within the pre-ovulatory period, levonorgestrel prevents follicular development and egg release by blocking the LH surge. It is typically used at a higher dose all at once or split between two doses. They can be taken up to 5 days after unprotected intercourse, however, they are the most effective within 72 hours (prevents ≥74% of pregnancies). 

The progestin-only implants and IUDs have higher efficacy rates than POPs due to their longer-acting nature, however, all of these devices have their own advantages and disadvantages that might sway patients and/or clinicians one way or the other. A side effect to be aware of with all of these progestin-only contraceptives is breakthrough bleeding and intermittent amenorrhea. Other common side effects include weight gain, headaches, and decreased libido. I have created a comparison table of progestin-only products currently available (in the US) for your reference. 

Progestin	Brand Names	Device/Route	Dose	Advantages	Disadvantages
Norethindrone	Micronor; Errin; Camila; Heather; Jencycla; Incassia	Oral pill	0.35 mg daily x 28 days; no placebo	No mineralocorticoid activity/hyperkalemia risk	Androgenic Low flexibility w/ adherence
Drospirenone	Slynd	Oral pill	4 mg daily x 24 days; placebo x 4 days	Anti-androgenic Flexibility w/ adherence	Hyperkalemia risk
Depot-medroxy-progesterone acetate	Depo-Provera	SQ injection	104 mg every 3 months	Can be given up to 2 weeks late w/o backup contraception Has shown reduced seizures in females w/ epilepsy	Black box warning for osteoporosis/ decreased BMD Delayed return of fertility (average conception ~10 months after last injection)
Etonogestrel	Nexplanon	Subdermal implant	68 mg slowly released over 3+ years	Long-acting, reversible Highly effective Low adherence concern Approved for 3 years, data suggests up to 5 is OK	Pain with insertion
Levonorgestrel	Mirena; Liletta; Skyla; Kyleena	Intrauterine device (IUD)	13.5-52 mg slowly released over 3-5 years (varies per product)	Long-acting, reversible Highly effective Low adherence concern Not associated with decreased efficacy in obese women Fewer systemic side effects Less breakthrough bleeding	Pain with insertion Controversial/rare infection risk
Levonorgestrel	Plan B; Next Choice; generics	Oral pill	0.75 mg; repeat in 12 hours OR 1.5 mg once	Can be used up to 5 days after intercourse (most effective w/in 72 hours) Repeat dosing OK in same cycle Not known to harm fetus if pregnant	May cause early next menses Strong CYP3A4 substrates may decrease effectiveness if used up to 28 days prior (i.e, barbiturates, topiramate, etc) Plan B One-Step may be less effective in obese women

Article written by: Hannah Wetter, PharmD Candidate in collaboration with Eric Christianson, PharmD, BCPS, BCGP

References:

1. Centers for Disease Control and Prevention. Selected Practice Recommendations. MMWR 2016; 65(4). 
2. Centers for Disease Control and Prevention. Summary Chart of U.S. Medical Eligibility Criteria for Contraceptive Use. Published 2016. Accessed via https://www.cdc.gov/reproductivehealth/contraception/pdf/summary-chart-us-medical-eligibility-criteria_508tagged.pdf
3. Kaunitz, A. Progestin-only pills (POPs) for contraception. UpToDate [web]. Last updated September 2021. Accessed via https://www.uptodate.com/contents/progestin-only-pills-pops-for-contraception?search=progestin%20only%20pills&source=search_result&selectedTitle=2~59&usage_type=default&display_rank=1
4. Turok, D. Emergency contraception. UpToDate [web]. Last updated October 2021. Accessed via https://www.uptodate.com/contents/emergency-contraception?search=emergency%20contraception&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H2285147330
5. Zigler, R., and McNicholas, C. Unscheduled vaginal bleeding with progestin-only contraceptive use. Am J Obstet Gynecol. Published 2016; 216(5):443-450.