The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. It is the oral form of combined hormonal contraception. The pill contains two important hormones: a progestin (a synthetic form of the hormone progestogen/progesterone) and estrogen. When taken correctly, it alters the menstrual cycle to eliminate ovulation and prevent pregnancy.
Combined oral contraceptive pills were first approved for contraceptive use in the United States in 1960, and remain a very popular form of birth control. They are used by more than 100 million women worldwide including about 9 million women in the United States. From 2015 to 2017, 12.6% of women aged 15–49 in the US reported using combined oral contraceptive pills, making it the second most common method of contraception in this age range (female sterilization is the most common method). Use of combined oral contraceptive pills, however, varies widely by country, age, education, and marital status. For example, one third of women aged 16–49 in the United Kingdom use either the combined pill or progestogen-only pill (POP), compared with less than 3% of women in Japan (as of 1950–2014).
Combined oral contraceptives are on the World Health Organization's List of Essential Medicines. The pill was a catalyst for the sexual revolution.
Background
Oral contraceptives
Hormonal oral contraceptives are preventive medications taken orally by females to avoid pregnancy by manipulating their sex hormones. The first oral contraceptive was approved by the US Food and Drug Administration (FDA) and sold to the market in 1960. There are two types of hormonal oral contraceptives, namely combined oral contraceptives and progesterone-only pills. Oral contraceptives, whether combined or progesterone-only, can effectively prevent pregnancy by regulating hormonal changes in the menstrual cycle, inhibiting ovulation, and altering cervical mucus to impede sperm mobility; combined pills have extra effects in menstrual cycle regulation and menstrual pain relief. Common off-label uses include menstrual suppression and acne relief, with combined oral contraceptives having additional benefits in relieving menstrual migraines.
Variants
Progesterone-only pills (POPs) utilise progestin, the synthetic form of progesterone, as the only active pharmaceutical ingredient in the formulation. In the US, drospirenone and norethindrone are the most commonly used compounds in formulations.
Combined oral contraceptives (COCs) are commonly classified into generations, referring to their order of development in history. This discussion may also help identify some key features in a variety of products. According to the European Medicines Agency, the first generation of combined oral contraceptives, which made use of a high concentration of estrogen only, were those invented in the 1960s. In the second generation of products, progestogens were introduced into the formulation while the concentration of estrogen was reduced. Starting from the 1990s, the progression in the development of combined oral contraceptives has been directed towards varying the type of progestogen incorporated. These products are referred as the third and fourth generation.
Estrogen ingredients: estradiol, ethinylestradiol, estetrol.
1st generation progestin: norethindrone acetate, ethynodiol diacetate, lynestrenol, norethynodrel.
2nd generation progestin: levonorgestrel, dl-norgestrel.
3rd generation progestin: norgestimate, gestodene, desogestrel.
The menstrual cycle
Hormonal oral contraceptives (HOCs) interact with hormonal changes in the menstrual cycle in females to prevent ovulation, and hence achieve contraception. In a 28-day menstrual cycle, there are the proliferative phase, ovulation, and then the secretory phase.
Menstruation marks the beginning of proliferative phase in day 1-14. In this period, the pituitary gland located near the brain secretes follicle-stimulating hormone (FSH) into the bloodstream to signal the development of follicle in ovary in the female reproductive system. While follicle serves as the chamber of ovum development, it secretes estrogen, a hormone that not only triggers the thickening of uterine lining in preparation for implantation, but also inhibits the secretion of FSH in pituitary via a negative feedback mechanism.
Specifically in ovulation, transient positive feedback by estrogen on FSH and luteinizing hormone (LH) secretion from pituitary is permitted so that the release of mature ovum from follicle is triggered.
In secretory phase on day 14-28, this follicle then transforms into corpus luteum and continues releasing estrogen with progesterone into bloodstream. While estrogen and progesterone primarily aid the maintenance of thickness in uterine lining, the negative feedback in pituitary allows them to inhibit FSH and LH secretion. In the absence of LH, corpus luteum degenerates and ultimately causes blood estrogen and progesterone levels to decline. Without these thickness maintaining agents, uterine lining breaks down and hence the presentation of menstruation.
Mechanism of action
Progesterone and estrogen, either in combination or with progesterone alone, are the active ingredients found in a hormonal oral contraceptive formulation. These medications are orally administered for systemic absorption to exert their effects. An artificially enhanced level of Progesterone throughout the menstrual cycle inhibits the pituitary secretion of FSH and LH such that their actions in stimulating follicular development and ovulation are prevented. Similarly, a boosted estrogen level activates the negative feedback mechanism in reducing FSH secretion from pituitary and therefore prevents follicular development. In the absence of a developed follicle, ovulation cannot occur so that fertilisation is made impossible and contraception is achieved. In comparison, progesterone is more efficacious than estrogen not only because of its additional action in impeding LH, but also its ability to modulate the cervical mucus into sperm-repellent.
Combined oral contraceptive pills were developed to prevent ovulation by suppressing the release of gonadotropins. Combined hormonal contraceptives, including combined oral contraceptive pills, inhibit follicular development and prevent ovulation as a primary mechanism of action.
Under normal circumstances, luteinizing hormone (LH) stimulates the theca cells of the ovarian follicle to produce androstenedione. The granulosa cells of the ovarian follicle then convert this androstenedione to estradiol. This conversion process is catalyzed by aromatase, an enzyme produced as a result of follicle-stimulating hormone (FSH) stimulation. In individuals using oral contraceptives, progestogen negative feedback decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the secretion of FSH and greatly decreases the secretion of LH by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH secretion prevent a mid-cycle LH surge. Inhibition of follicular development and the absence of an LH surge prevent ovulation.
Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding), but was also found to inhibit follicular development and help prevent ovulation. Estrogen negative feedback on the anterior pituitary greatly decreases the secretion of FSH, which inhibits follicular development and helps prevent ovulation.
Another primary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration through the cervix into the upper genital tract (uterus and fallopian tubes) by decreasing the water content and increasing the viscosity of the cervical mucus.
The estrogen and progestogen in combined oral contraceptive pills have other effects on the reproductive system, but these have not been shown to contribute to their contraceptive efficacy:
- Slowing tubal motility and ova transport, which may interfere with fertilization.
- Endometrial atrophy and alteration of metalloproteinase content, which may impede sperm motility and viability, or theoretically inhibit implantation.
- Endometrial edema, which may affect implantation.
Insufficient evidence exists on whether changes in the endometrium could actually prevent implantation. The primary mechanisms of action are so effective that the possibility of fertilization during combined oral contraceptive pill use is very small. Since pregnancy occurs despite endometrial changes when the primary mechanisms of action fail, endometrial changes are unlikely to play a significant role, if any, in the observed effectiveness of combined oral contraceptive pills.
Oral contraceptives come in a variety of formulations, some containing both estrogen and progestins, and some only containing progestin. Doses of component hormones also vary among products, and some pills are monophasic (delivering the same dose of hormones each day) while others are multiphasic (doses vary each day). combined oral contraceptive pills can also be divided into two groups, those with progestins that possess androgen activity (norethisterone acetate, etynodiol diacetate, levonorgestrel, norgestrel, norgestimate, desogestrel, gestodene) or antiandrogen activity (cyproterone acetate, chlormadinone acetate, drospirenone, dienogest, nomegestrol acetate).
Combined oral contraceptive pills have been somewhat inconsistently grouped into "generations" in the medical literature based on when they were introduced.
- First generation combined oral contraceptive pills are sometimes defined as those containing the progestins noretynodrel, norethisterone, norethisterone acetate, or etynodiol acetate; and sometimes defined as all combined oral contraceptive pills containing ≥ 50 μg ethinylestradiol.
- Second generation combined oral contraceptive pills are sometimes defined as those containing the progestins norgestrel or levonorgestrel; and sometimes defined as those containing the progestins norethisterone, norethisterone acetate, etynodiol acetate, norgestrel, levonorgestrel, or norgestimate and < 50 μg ethinylestradiol.
- Third generation combined oral contraceptive pills are sometimes defined as those containing the progestins desogestrel or gestodene; and sometimes defined as those containing desogestrel, gestodene, or norgestimate.
- Fourth generation combined oral contraceptive pills are sometimes defined as those containing the progestin drospirenone; and sometimes defined as those containing drospirenone, dienogest, or nomegestrol acetate.
Medical use
Contraceptive use
Combined oral contraceptive pills are a type of oral medication that were originally designed to be taken every day at the same time of day in order to prevent pregnancy. There are many different formulations or brands, but the average pack is designed to be taken over a 28-day period (also known as a cycle). For the first 21 days of the cycle, users take a daily pill that contains two hormones, estrogen and progestogen. During the last 7 days of the cycle, users take daily placebo (biologically inactive) pills and these days are considered hormone-free days. Although these are hormone-free days, users are still protected from pregnancy during this time.
Some combined oral contraceptive pill packs only contain 21 pills and users are advised to take no pills for the last 7 days of the cycle. Other combined oral contraceptive pill formulations contain 91 pills, consisting of 84 days of active hormones followed by 7 days of placebo (Seasonale). Combined oral contraceptive pill formulations can contain 24 days of active hormone pills followed by 4 days of placebo pills (e.g. Yaz 28 and Loestrin 24 Fe) as a means to decrease the severity of placebo effects. These combined oral contraceptive pills containing active hormones and a placebo/hormone-free period are called cyclic combined oral contraceptive pills. Once a pack of cyclical combined oral contraceptive pill treatment is completed, users start a new pack and new cycle.
Most monophasic combined oral contraceptive pills can be used continuously such that patients can skip placebo days and continuously take hormone active pills from a combined oral contraceptive pill pack. One of the most common reasons users do this is to avoid or diminish withdrawal bleeding. The majority of women on cyclic combined oral contraceptive pills have regularly scheduled withdrawal bleeding, which is vaginal bleeding mimicking users' menstrual cycles with the exception of lighter menstrual bleeding compared to bleeding patterns prior to combined oral contraceptive pill commencement. As such, a study reported that out of 1003 women taking combined oral contraceptive pills approximately 90% reported regularly scheduled withdrawal bleeds over a 90-day standard reference period. Withdrawal bleeding usually occurs during the placebo, hormone-free days. Therefore, avoiding placebo days can diminish withdrawal bleeding among other placebo effects.