The overturning of Roe v. Wade in June 2022, which is the case that set a precedent for federally-protected abortions during the first trimester, after the hearing of the case Dobbs v. Jackson Women's Health Organization, allows individual states to determine the legality of abortion within their jurisdiction.^1 After the overturning, several states had trigger laws in place to make abortion illegal at different points within the pregnancy, with the most restrictive being illegal at any point, for any reason (except to save the life of the pregnant person).^1 The repercussions of these laws go further than many of us realized at first. Beyond more and more laws being proposed that limit reproductive freedom, the banning of abortifacient drugs could have impacts on other common drugs whose exact mechanism of action is unknown. This was the case for levonorgestrel, the active ingredient in Plan B.
What is levonorgestrel?
Levonorgestrel is a synthetic progestin used in many common birth controls and emergency contraceptives. Notably, it is the active ingredient in many emergency contraceptives such as Plan B, Julie, and EContra EZ. As a combined oral contraceptive pill (COC), it is used in combination with various synthetic estrogens in brands such as Vienva and Sronyx. It is also the active ingredient in all hormonal intrauterine devices (IUDs), such as Mirena and Skyla. It has a very similar structure to the naturally-produced hormone progesterone and can bind to the progesterone receptor to induce similar effects.^2 However, the structural differences in levonorgestrel and progesterone allow levonorgestrel to be better absorbed by the body with a longer half-life, making it a more desirable drug.^2
Mechanism of Action
In a normal menstrual cycle, hormone levels rise and fall to induce different effects on the ovaries and uterus throughout the month. Menstruation occurs at the start of the cycle when levels of estrogen and progesterone are low.^3 These low levels cause Gonadotropin-Releasing Hormone (GnRH) to be released from the hypothalamus in more frequent pulses.^3 GnRH causes the pituitary gland to release Follicle-Stimulating Hormone (FSH), which stimulates the growth of follicles (fluid-filled sacs that contain an egg) in the ovary, which release estrogen.^4 Over time, one follicle becomes the dominant follicle, and the others break down.4 The higher levels of estrogen encourage the endometrium, or uterine lining, to thicken.^4 Eventually, when estrogen levels become high enough, they induce a surge of Luteinizing Hormone (LH), which causes the dominant follicle to rupture, releasing the egg.^4 This is called ovulation, and the egg is now ready to be fertilized. The ruptured follicle then forms a structure called the corpus luteum and begins releasing progesterone.^4 The progesterone causes the endometrium and cervical mucus to thicken further to provide fluids and nutrients for the possible embryo and prevent other sperm and bacteria from entering the uterus.^4 Over time, if no implantation occurs, the corpus luteum degenerates, and progesterone and estrogen levels drop, inducing menstruation.^4
However, when levonorgestrel binds to the progesterone receptor, the resulting complex turns on genes that slow the release of GnRH.^5 Without the more frequent pulses of GnRH, FSH and the LH surge are blocked, which prevents ovulation.^5 If no ovulation occurs, no egg is released to be fertilized. This is the mechanism that emergency contraceptives, which have a higher dose of levonorgestrel, rely on. The goal is that by delaying ovulation, any sperm (which can live for up to 5 days within the female body) present from unprotected sex will not have anything to fertilize. The dose available in IUDs is not high enough to stop ovulation in everyone.^6 When taken consistently (such as in an IUD), the simulated effects of progesterone cause the cervical mucus to thicken, increasing the difficulty for sperm to enter the uterus and preventing fertilization from occurring.^6
The previous two mechanisms are well understood. However, until recently, scientists were unsure if levonorgestrel affected the implantation of an embryo into the uterine lining. If levonorgestrel did show signs of preventing fertilization or interrupting development after fertilization, it would be at risk of becoming banned in certain states due to having abortifacient properties.^7 This possible mechanism was difficult to study since the human ovum is not visible during the roughly 9-day period from the time of fertilization til the implantation of the blastocyte into the endometrium.^7 However, through clever studies, it was shown that taking levonorgestrel on the day before ovulation effectively prevented pregnancy, while taking it the day of or after ovulation did not prevent pregnancy.^7 Therefore, there is no evidence that levonorgestrel interferes with pregnancy after fertilization has occurred.
Impacts
Because of these studies, as of December 23, 2022, the US Food and Drug Administration (FDA) has officially changed the drug facts label and consumer information leaflet for levonorgestrel to now state that it “does not terminate pregnancy.”^8 Furthermore, they have stated that “the current science supports the conclusion that Plan B One-Step works by inhibiting or delaying ovulation and the midcycle hormonal changes”, and that it has “no direct effect on fertilization or implantation”.^8 Because of this statement, there are no legal grounds to ban levonorgestrel due to possible abortifacient effects, meaning it will remain legal in all states. However, as laws regarding reproductive health options become stricter in some states, we may see Plan B and other emergency contraceptives face different restrictions, such as cost, OTC status, and age restrictions.
Sources
“What is Roe v. Wade? And other questions answered” International Planned Parenthood Foundation. 2022. https://www.ippf.org/blogs/roe-v-wade?gad_source=1&gclid=CjwKCAjwrcKxBhBMEiwAIVF8rJmxhiF5PojPczaZkKsiwTAwwcOlAL7-8LC3wGi8sY0ZY661j53gjRoC0ZAQAvD_BwE
Vrettakos, C, and Bajaj, T “levonorgestrel” StatPearls. 2023. https://www.ncbi.nlm.nih.gov/books/NBK539737/
Casteel, C and Singh, G “Physiology, Gonadotropin-Releasing Hormone” StatPearls. 2023. https://www.ncbi.nlm.nih.gov/books/NBK558992/
Laughlin, J “Menstrual Cycle” Merck Manual. 2022. https://www.merckmanuals.com/home/women-s-health-issues/biology-of-the-female-reproductive-system/menstrual-cycle
García-Sáenz, Manuel et al. “Understanding Progestins: From Basics to Clinical Applicability.” Journal of clinical medicine vol. 12,10 3388. 10 May. 2023, doi:10.3390/jcm12103388
“Levonorgestrel” DrugBank Online. 2024. https://go.drugbank.com/drugs/DB00367
Adashi EY, Cohen IG, Wilcox AJ. The FDA Declares Levonorgestrel a Nonabortifacient—A 50-Year Saga Takes a Decisive Turn. JAMA Health Forum. 2023;4(8):e232257. doi:10.1001/jamahealthforum.2023.2257
“Plan B One-Step (1.5 mg levonorgestrel) Information” US Food and Drug Administration. 2022. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/plan-b-one-step-15-mg-levonorgestrel-information