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Reproductive Health

Mechanisms of the Contraceptive Action of Hormonal Methods and Intrauterine Devices (IUDs)

 

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Modern methods of contraception have had an important impact in improving the health of women and children. However, in certain countries or regions of the world, incorrect and intentionally misleading information about the mechanism of action of these contraceptive methods has proliferated. This summary, originally created for distribution in Latin America, reviews the scientific evidence concerning the mechanisms of action.

The introduction in the last few decades of modern methods of contraception has had an important impact in improving the health of women and children.1 However, in certain countries or regions of the world, incorrect and intentionally misleading information about the mechanism of action of these contraceptive methods has proliferated. These contraceptive methods prevent pregnancy; they do not terminate an already established pregnancy. There is no scientific evidence to support the claim that the hormonal contraceptive methods and IUDs have an abortifacient action. Actually, in current medical practice the presence of a pregnancy is considered an absolute contraindication to initiate the use of any of these methods.2

Understanding how modern contraceptives work is fundamentally important. Providers should be prepared to describe the mechanisms of action to women considering the use of these methods. Similarly, women need to know how contraceptives work in order to make a truly informed choice and to use the methods correctly. Substantial misinformation on this subject exists worldwide, among policy makers, providers, users and the public at large.

This paper will review the evidence concerning the mechanisms of action of modern hormonal contraceptives and intrauterine devices (IUDs). Most methods have more than one potential mechanism of action. For example, combined oral contraceptives are highly effective in preventing ovulation (egg release). However, should ovulation occur, fertilization is still unlikely due to the effect of oral contraceptive hormones on thickening the cervical mucus, impairing sperm penetration. One cannot say with certainty what the contribution of various contraceptive effects may be for a given woman. However, existing evidence does not support claims that either hormonal methods or the IUD are abortifacients or prevent implantation.

Hormonal Methods

Combined Oral Contraceptives (COCs)

The primary mechanism of action of COCs is the inhibition of ovulation. The release of an egg, which commonly occurs in the middle of the menstrual cycle, is prevented by COCs. Two hormones produced by the pituitary, a gland located at the base of the brain, coordinate the development and release of an egg from the ovary. One is follicle stimulating hormone, abbreviated FSH, and the other is luteinizing hormone, or LH. A surge in both of these hormones ordinarily occurs in the middle of a woman's menstrual cycle. The surge in LH is the trigger for ovulation. COCs inhibit the production of both FSH and LH and consequently prevent ovulation.3

In the very rare cases where ovulation may occur, another contraceptive mechanism of COCs acts to prevent fertilization. COCs have an effect on the cervical mucus. The progestin contained in COCs causes the cervical mucus to become thick and prevents sperm penetration; the sperm can not pass through the cervix and fertilization cannot take place.4

Progestin-only Methods

Progestin-only Pills (POPs)

Progestin-only pills (POPs) prevent pregnancy through a combination of actions. The amount of progestin in POPs is much less than in COCs; because of this, POPs do not consistently prevent ovulation. Indeed, about 40 percent of women using POPs may ovulate. When POPs inhibit ovulation they do so in the same manner described for COC.3

Another mechanism of action accounts for the high efficacy of these pills. This mechanism is the alteration of the cervical mucus. Progestin-only contraceptives cause a "hostile" cervical mucus. POPs greatly reduce the volume of mucus, increase its viscosity and cell content, and alter its molecular structure. These actions result in little or no sperm entry to the uterine cavity. Even in the rare cases when penetration does occur, sperm motility may be reduced and fertilization is very unlikely to take place.5

The use of POPs is mostly recommended for breastfeeding women, because combined hormonal methods reduce the production of breastmilk. During the period of amenorrhea (absence of menstruation) associated with breastfeeding, ovarian function is largely suppressed; ovulation is unlikely to occur and the cervical mucus is hostile to the sperm.6 These effects greatly enhance the contraceptive action of POPs during breastfeeding.

Injectables (DMPA)

The most widely used injectable contraceptive is depo-medroxyprogesterone acetate (DMPA), a long-acting, injectable progestin. The contraceptive action of DMPA occurs primarily at the level of the pituitary and the hypothalamus. As with COCs, DMPA interrupts the usual hormonal messages sent from the brain to the ovary that lead to ovulation. Specifically, DMPA prevents the mid-cycle surge of LH, which is necessary for ovulation.7

As with other progestin-only methods, DMPA also has an effect on the cervical mucus; the mucus becomes scanty and thick which makes it unfavorable for sperm penetration.5

Soon after the first injection of DMPA, the endometrium starts becoming thin and underdeveloped. Under these circumstances, DMPA could, theoretically, inhibit implantation. However, DMPA is highly effective in preventing ovulation and sperm penetration and the possibility of fertilization taking place is negligible. There is no data available to support prevention of implantation as a contraceptive action of DMPA or any of the other currently available hormonal contraceptives, including pills and implants.

Other injectable contraceptives are available in some countries. Another progestin-only injectable product is norethisterone enanthate (NET EN or Noristerat), which is given every two months. In addition, three types of combined injectable contraceptives, which are given every month, are available in some countries. These latter methods, like COCs, contain both a progestin and an estrogen. The progestin-only injectable works like DMPA,8 while the combined injectable contraceptives act mainly like COCs.9

Implants

Progestins can also be administered from implants placed under the skin. The progestin used currently is levonorgestrel (Norplant® implants), which is also found in some COCs and POPs. The contraceptive effect of the levonorgestrel implants is similar to that of the POPs. Ovulation occurs in about 10 percent of cycles in the first year. With time, blood levels of the progestin decline, and ovulation occurs more often (30 percent to 75 percent of cycles).10

However, like other hormonal methods, implants thicken the cervical mucus. This prevents sperm from getting into the uterus and makes fertilization of the egg unlikely. The changes in the cervical mucus are more consistent compared with POPs.11

Hormonal Method Mechanisms
Ovulation
graphic of pituitary glandPituitary gland

Hormonal methods disrupt the balance of natural hormones, blocking hormonal signals from the hypothalamus and pituitary gland near the brain that are necessary for ovulation. However, progestin-only methods do not always block ovulation.

Cervical Mucus
graphic of cervical canalCervical canal

Cervical mucus normally fluctuates in thickness throughout a woman's cycle, becoming thin and watery at the peak of fertility. Hormonal methods keep the mucus thick all the time, making it difficult for sperm to get through. For progestin-only methods, this mechanism accounts for their high efficacy.

IUD Mechanisms
Affects Sperm
graphic of uterine cavityUterine cavity

IUDs prevent sperm from reaching the uterine cavity and the fallopian tubes, where fertilization occurs. A foreign-body reaction in the uterine cavity to an IUD causes cellular and biochemical changes that may be toxic to sperm. Also, the copper in copper IUDs may be toxic to sperm.

Intrauterine Devices (IUDs)

Despite years of study, the precise mechanism of contraceptive action of intrauterine devices (IUDs) remains somewhat unclear. Relevant investigations in humans are difficult to conduct, and extrapolating from animal studies is not always meaningful. The high efficacy of IUDs in humans may stem from more than one mechanism of action. This section will summarize the evidence concerning potential mechanisms of action in humans and describe the conclusions of expert panels on this issue.

Effects on sperm

IUDs, especially the now most widely used copper containing IUDs (TCu-380A and Multiload) hinder ascent of sperm to the fallopian tubes (where fertilization occurs) or reduce the ability of sperm to fertilize an egg. Several studies have shown that IUDs influence the number of sperm reaching the uterine cavity and the fallopian tubes. The sterile foreign-body reaction in the uterine cavity causes both cellular and biochemical changes that may be toxic to sperm. There is also evidence that the copper released from the IUDs may have a toxic effect on the sperm.

Investigators have done flushing studies of the uterine cavity and fallopian tubes after exposure to semen. Women using IUDs had lower concentrations of sperm in the uterus and tubes than did women not using IUDs. In addition, the sperm found in women using copper IUDs were likely to be damaged and not able to fertilize.12 Thus, the evidence suggests that fewer sperm reach the site of fertilization in women using IUDs than in women who are not using the device, and, for women using copper devices, the sperm may not be able to fertilize the egg. This effect on the sperm is considered the main mechanism of the IUD's contraceptive action.

Early developmental events

No contraceptive method is perfect, but the efficacy of IUDs is exceptionally good -- 99 percent effective for copper IUDs. Most studies of early pregnancy rates have relied on sensitive measurements of serum beta-hCG, a hormone produced by the fertilized egg near the time of implantation and thereafter. Using this marker, a large number of studies indicate that women using IUDs rarely show evidence of fertilization, and some of these cases may result in an early embroyonic loss, a natural occurrence. One study using a more sensitive assay found a transient rise and fall of beta-hCG in only 1 percent of IUD users, supporting other studies that have estimated copper IUD effectiveness at 99 percent.13 However, among couples trying to conceive, early embryonic loss is very high, ranging from 8 percent to 57 percent.13 Whether the rate of this natural early embryonic loss among IUD users is similar to that in other women is unknown.

Microscopic evidence of fertilization

Microscope studies provide further evidence of the contraceptive effect of IUDs. Fertilized eggs are found in the fallopian tubes and in the uterine cavity with predictable frequencies in women who are sexually active and not using contraception. The rate of recovery of fertilized eggs from the fallopian tubes of copper IUD users is much lower than that in sexually active women who are not using a contraceptive method. Furthermore, in studies searching for eggs, no fertilized eggs have been found in the uterine cavity in copper IUD users.14

Implications of ectopic pregnancy rates

If the mechanism of action of IUDs was to prevent implantation of fertilized eggs in the uterine cavity, then rates of ectopic pregnancy (pregnancy in the fallopian tubes) should be unaffected by IUD use. In contrast, inert and copper-bearing IUDs confer powerful protection against tubal pregnancies.15 This fact strongly suggests that these IUDs prevent fertilization from occurring or have a contraceptive effect that extends beyond the uterus to include the fallopian tubes as well.

Is the IUD an abortifacient?

Some people incorrectly believe that the principal mechanism of action of IUDs is prevention of implantation of fertilized eggs.16 The existing evidence does not support the theory that the mechanism of action of IUDs includes the destruction of embryos in the uterus. The foreign body reaction induced by copper and inert IUDs is hostile to sperm and possibly eggs in the upper genital tract. Few sperm reach the site of fertilization in the fallopian tubes, and those that do are unlikely to be capable of fertilizing an egg. Eggs may be similarly impaired. Should fertilization occur, the chances for establishing a pregnancy likely decrease as the fertilized egg approaches the uterine cavity. Thus, the IUD appears to work at a much earlier stage of human reproduction than was previously thought; prevention of fertilization seems to be the dominant mode of action.

As noted by the World Health Organization Scientific Group:17 "It is unlikely that the contraceptive efficacy of IUDs results, mainly or exclusively, from their capacity to interfere with implantation; it is more probable that they exert their antifertility effects beyond the uterus and interfere with steps in the reproductive process that take place before the ova reach the uterine cavity." Similarly, the American College of Obstetricians and Gynecologists18 reviewed the evidence and concluded that, "As such, the IUD is not an abortifacient".

Pills for Emergency Contraception

Combined oral contraceptive pills (COCs) are the most commonly used method of emergency contraception. High doses of POPs can also be used for this purpose. The precise mechanism of action is not clear, especially with regard to mechanisms other than interfering with ovulation. If used before ovulation, the main mechanism of action is the suppression or delay of ovulation; as a result, fertilization is prevented.19

Some studies have described slight changes in the endometrium, but it is not clear if these histological changes would prevent implantation.20 Other studies, however, have shown an absence of endometrial changes.21 If emergency contraceptive pills are taken after the estimated time of implantation, they are no longer effective and pregnancy continues unaffected.22 Stated alternatively, emergency contraception prevents pregnancy from starting. It cannot cause an abortion once pregnancy is established.

Contraceptive Failures and Duration of the Contraceptive Effect

Most accidental pregnancies that occur while using the modern methods of contraception are due to the incorrect and inconsistent use of the method. However, in a small percentage of cases, an accidental pregnancy may also occur while the method is used correctly and consistently. Therefore, fertilization, implantation and a normal pregnancy are certainly possible during contraceptive use.

Concerns are sometimes expressed about the duration of the contraceptive effect and the return of fertility once the use of the method is discontinued. As a matter of fact, the return of fertility is very fast. Ovulation may occur immediately after discontinuing the use of oral contraceptives, combined injectables and IUDs. There is a delay in the return of fertility upon discontinuation of progestin-only injectables, namely DMPA. As an average, pregnancy occurs within 9 to 10 months after the last DMPA injection and by 15 months the pregnancy rates are the same for previous DMPA users and for non-users.23

Comment

The World Health Organization Scientific Group noted the widespread confusion over terminology of early reproductive events. To clarify this issue, they suggested the following definitions: "Fertilization is the process that begins with the penetration of the secondary oocyte by the spermatozoon and is completed shortly before the first cleavage. It usually takes up to 24 hours to complete in humans." In addition, "Implantation is the process that starts with the attachment of the zona-free blastocyst (fertilized egg) to the uterine wall (days 5-6 post-fertilization); the blastocyst then penetrates the uterine epithelium and invades the stroma. The process is complete when the blastocyst develops primary villi and the surface defect on the epithelium is closed (days 13-14 post-fertilization)." In the United States, the Code of Federal Regulations of the Department of Health and Human Services states that "pregnancy encompasses the period of time from confirmation of implantation (through any of the presumptive signs of pregnancy, such as missed menses, or by a medically acceptable pregnancy test), until expulsion or extraction of the fetus."

Stated alternatively, pregnancy begins when implantation is complete (about two weeks after fertilization in humans). Fertilization does not establish a pregnancy. Rather, fertilization is a necessary but insufficient step on the path to pregnancy. Any method of fertility regulation that acts before implantation is not an abortifacient, since no pregnancy exists. Major medical organizations, such as the World Health Organization, and the American College of Obstetricians and Gynecologists concur on this biological point.

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