by Leontine Bakermans MSc PharmD
Coordinator One of Us, Netherlands

Introduction

The birth control pill came on the market in the middle of the last century as a new remedy for menstrual disorders, such as painful or irregular periods, and it is still prescribed for these indications, usually for a short time. But what was first described as a side effect ("you can become infertile") quickly became the main indication.

The pill is now used by millions of women around the world. In the field of family planning, the pill is also presented as the instrument par excellence for the emancipation of women. Its use is promoted at all levels, such as the proposal of the Council of Europe with the resolution 'Strengthening women: promoting access to contraception in Europe' (1) and the UN population fund (UNFPA) (2).

However, there seems to be a turnaround, the number of women taking the pill is decreasing. This is because there are also negative sides of pill use, about which more and more is known.

Types of pills

There are different types of oral contraceptive pills. The most commonly used pills are the so-called combination pills and the pill with progestogen only, or the mini pill. This article is limited to the combination pill, which is most commonly used. At the end the morning-after pill and abortion pill will be discussed. The combination pill contains two artificial sex hormones: an estrogen and a progestogen. The pills can be further distinguished into so-called 2nd and 3rd generation pills. The 2nd generation pills contain levonorgestrel and norgestimate as progestogen and the 3rd generation pills contain e.g desogestrel. The estrogen is almost always ethinylestradiol.

The pill is swallowed for 21 days, after which nothing or seven placebo pills are taken for seven days During these seven days, what is called a “withdrawal bleed” occurs; it is not a real period. Because of these monthly hemorrhages, it seems as if there is a normal cycle, but this is a fake cycle.

The normal cycle

What happens during a normal cycle is summarized in the figure below:

Figure 1

The sex hormones oestradiol and progesterone are regulated from the brain (hypothalamus and pituitary) and via the ovaries:

• The brain measures the amount of sex hormones circulating in the blood.
• The pituitary gland uses this to produce the hormones LH and FSH, which, in turn, send messages to the ovaries to produce the sex hormones (3).

Because of this:

• Due to the increase in progesterone, the endometrium becomes thicker and is well blooded. This is necessary to allow any fertilized egg to implant. If no egg is fertilized, no implantation takes place and the thick endometrium is rejected: menstruation. After this, another egg matures in the ovary and the whole cycle starts again (if a pregnancy takes place, the amount of progesterone remains high, as this is necessary to maintain the pregnancy).
• The mucus in the cervix becomes thinner, which makes it easier for sperm to progress. This is also one of the symptoms used by natural birth control methods, as this phenomenon is usually easy to detect yourself.
• But female sex hormones also influence emotions like attraction to the opposite sex, stress, hunger, behavior, friendships, aggression and how you feel (4).

Mechanism action of the pill

The effect of the pill is based on the same principles as the hormones in the normal cycle, but in the opposite direction (5). The artificial hormones in the pill weaken the signal given by the brain and this stops the natural cycle. The body itself no longer produces natural estradiol and progesterone, with the result that

• No more egg cells mature and no more eggs are released. This is the intended main effect of the pill, because it prevents fertilization and pregnancy
• The uterine lining does not thicken and is therefore unsuitable for the implantation of a fertilized egg
• Cervical mucus becomes more difficult for sperm to penetrate

Side effects

Abortifacient effect?

To reduce side effects, the dosage of estrogens and progestogens in the pill has been reduced. The decreasing dosage of the pill has a direct effect on the effectivity and of course, a minimal amount of active ingredient is needed for a drug to have an effect. As a result, the main effect may no longer be 100% and egg ripening and ovulation are not always stopped. An egg can then still be released that could be fertilized. If this fertilized egg is implanted in the uterus despite the fact that the pill makes implantation more difficult, we have an ongoing pregnancy, despite taking the pill. But it is also possible that the fertilized egg cannot implant in the uterus, because the pill has not made the uterine mucosa suitable for it. The fertilized egg is then destroyed and the pill works as an abortifacient.

In practice there are a number of factors that reduce the efficacy of the pill. There are situations in which too little of the active substance from the tablet becomes available in the body, for example due to certain interactions with other medicines or diarrhea, or because a number of women have difficulty taking the pill consequently every day. Certain genes may also cause increased degradation. How often does an early abortion occur? There are no exact numbers, we can only say that it cannot be excluded that it happens (6,7).

Cancer

Because research shows that some types of cancer depend on naturally occurring hormones for their development and growth, a lot of research has been done into the relationship between hormones in the pill and cancer. A study showed that taking the pill for more than 8 years showed an increased risk of cancer (8). By the way, the pill has a protective effect against cancer of the lining of the uterus and ovaries, but these types of cancer are very rare by nature and an improvement of a very small amount is still very small. The U.S. government has therefore added estrogens contained in the pill to the official list of carcinogens (9) and the WHO has also classified the pill as a group 1 (the heaviest type) carcinogen for breast, cervical and liver cancer (10). This is the same category as for tobacco and asbestos.

Breast cancer

The risk for a woman to get breast cancer depends on several factors, including a link with pill use, because estrogens affect breast tissue. The risk increases from 1.1 times higher with 1 year of pill use to 1.6 times higher with 10 years of use. Further, this risk is higher if you start taking the pill at a young age, because when breast cell proliferative activity is high, there is more chance for mutations in DNA, so the susceptibility to genetic damage in breast epithelial cells becomes higher. Women who have an abnormality in one of the breast cancer genes even have a greatly increased risk of developing breast cancer (11,12,13).

Liver tumors

The pill plays a key role in the development of liver cell adenoma (benign tumor), usually after use for more than 5 years, but sometimes an adenoma develops as early as after 6 months of pill use. It occurs in about 3 out of every 100,000 pill users (15, 16).

Cervical cancer

Cervical cancer is the second most common type of cancer in females worldwide.

Human papillomavirus (HPV) is a group of viruses that are extremely common. Two HPV types (16 and 18) cause 70% of cervical cancers and pre-cancerous cervical lesions. HPV is mainly transmitted through sexual contact and most people are infected with HPV shortly after the onset of sexual activity. A condom gives insufficient protection because the virus is available in a broad zone around the sex organs. OC users might have more sex, with more partners higher chance of infection. Changes to cervical fluid caused by OC use may compromise one’s immunity higher susceptibility to HPV infection.

Women who take the pill for more than 5 years are twice likely to get cervical cancer. After 10 years, this can increase to a 3 times higher risk (17,18).

Osteoporosis

The amount of bone tissue in skeleton is known as bone mass and can keep growing until age 30. At that point, bones have reached their maximum strength known as peak bone mass (PBM). The PBM relates to lifetime fracture risk. Natural estrogen, plays an essential role in bone growth. By suppressing estrogen, as in OC-use, there is

a detrimental effect on the bone. In later life it increases the risk of brittle bones (osteoporosis) and therefore a rise in bone fractures (19).

Heart and blood vessels

Oral contraceptive hormones have an impact on the lipid and carbohydrate metabolism. They significantly affect plasma lipoprotein metabolism, which can raise the levels of plasma triglycerides, low-density lipoprotein, and high-density lipoprotein.

Taking the pill therefore increases the risk of thrombosis (the formation of a blood clot,

in a vein of the legs, lungs, heart (heart attack) or brain (stroke) 2 to 4 times (23, 24). The third-generation pills even give a 4 to 7 times higher risk of thrombosis (reason why they are now much less prescribed).

Myocardial infarction

Studies show that in young women taking the contraceptive pill more or less doubles the risk of having a stroke (20.21). Women who take both the pill and carry the variant of a certain coagulation factor gene are 20 times more likely to have a brain attack (22).

Lung embolism

In rare cases, a venous thrombosis or pulmonary embolism is fatal (26).

The risk of thrombosis when taking the pill is also greatly increased by the presence of risk factors such as smoking, age and obesity.

Psychological effects

In addition to effects on the ovaries, the sex hormones also influence emotional things like attraction, stress, hunger, behaviour, friendships, aggression and how you feel (4). Effects on this by suppressing the sex hormones through pill use is therefore inevitable, but only recently more clarity has become available. It appears that also the Hypothalamic-Pituitary-Adrenal axis (HPA axis) is involved. This axis also acts via the hypothalamus and pituitary gland, but with the adrenal glands as target organ. Via this axis, the renal glands release cortisol. Cortisol reacts to stress and regulates many body processes including, mood, emotions and sexuality. Sex steroids exert profound control over the HPA axis. Suppressing this system with artificial hormones, has an effect upon all the processes this axis regulates. The HPA axis continues to develop until after puberty.

A 2016 Danish study of women between the ages of 15 and 34 showed that among those who used hormonal contraceptives, there was a forty percent higher risk of taking antidepressants. Especially women between 15 and 19 years had a higher risk of becoming depressed (28). 

A link between pill use in young women and the risk of depression in adulthood has also been shown. This suggests that adolescence can be a sensitive period during which pill use can increase a woman's risk of depression, even years after use of the pill was stopped (29).

The Dutch researcher Estrella Montoya states: "It is almost certain that the pill has an effect on the brain, in areas that are important for mood, anxiety and pleasure (30).

In her book 'Your brain on the pill' (4), Sarah Hill, professor of psychology, describes new research on the effect on the brain and psychological influence of pill use. She came to the conclusion that by suppressing the natural hormone profile through pill use you can start to feel like a totally different person. This goes as far that, although the research is still in its very recent, this suggests that the pill could have an influence on who you find attractive (through pill use you could fall for a different type of man as without pill), on the dynamics of your relationships (pill extinguishes feelings of lust), how you react to the face of your partner, on your chances of ever getting divorced, etc.

MRI scans have recently shown that the size of certain parts of the brain, including the hypothalamus, was considerably smaller in women taking the pill than in women not taking it (31). And the hypothalamus is the organ from which the hormones are controlled. What effect this has in the longer term is still unknown.

Women under 19 years of age

The influence of sex hormones plays an enormous role in all gender-specific developments during puberty and adolescence, not only in the visible parts of the body, but also on the brain. Girls who are just menstruating are still busy with their brain development. Brain development is usually not finished until we are 20-25 years old. Sarah Hill advises against influencing your hormone balance with the pill before the age of nineteen or twenty and recommends more scientific research into the effects of the pill. Animal studies have found that hormones, especially when the brain is still developing, can irreversibly influence behavior. Adolescent girls have in addition a higher chance of getting breast cancer and reach a lower peak bone density with higher risk of fractures.

The morning-after pill

There are 2 types of morning-after pill available. One consists of the same progestogen as most commonly used in the pill: levonorgestrel. It can be taken up to 72 hours after unprotected sexual intercourse. Later, another one is added EllaOne® (ulipristal acetate). This is even effective up to 120 hours (5 days) after unprotected sexual intercourse. They are sold about 300,000 times a year in the Netherlands in a population of 17 million people (32).

The effect of the morning-after pill is partly based on ovulation inhibition, but if the pill is taken from the day before ovulation, i.e. in the most fertile period, ovulation can no longer be inhibited. If ovulation has already occurred, it can of course no longer be inhibited as well. In these cases, the efficacy is based on preventing implantation, an abortifacient effect (33).

The abortion pill

Despite contraception, many women get unplanned pregnancies. 60-70% of women who come for an abortion indicate that the unwanted pregnancy occurred despite the use of contraception (34).

The abortion pill is a series of 2 types of pills, to be taken 2 days in a row. The first pill to be taken, mifepristone, is an antiprogesterone drug, which suppresses the natural progesterone needed to maintain a pregnancy.  It loosens the baby. After 2 days another medicine has to be taken, prostaglandin, which causes the uterus to contract and expels the baby. This can be done up to ten weeks after the last menstruation in the U.S.

The abortion pill is not a simple and innocent remedy. It ends human life and it's not without risk. The leaflet therefore states that it is important to have access to appropriate medical care if an emergency situation arises and the patient must remain close to the treatment center (36). In addition, an ectopic pregnancy must first be excluded, because in that case the abortion pill does not work and medical intervention is required. Enormous cramps and heavy blood loss are common. Prolonged vaginal bleeding may occur. In some cases, severe bleeding may require surgical removal of the uterus. Rarely, the uterus may rupture or a fatal shock syndrome may result from a particular bacterium. Bleeding is in no way proof that the pregnancy has ended, because bleeding also usually occurs if the treatment fails. The non-negligible risk of failure (4.5 to 7.8% of cases) makes a control visit mandatory to check that the abortion has been completed. In case of an incomplete abortion, a curettage is still required to achieve complete abortion. A so-called "do it yourself abortion", which means that the pills are taken without medical supervision, can therefore have terrible consequences.

Abortion Pill Reversal

What if there is regret after the abortion pill? After taking the abortion pill, some women have regret and realize that they do want to keep their baby. If they have only taken the first pill, but have not yet started the medication for the following days, they are still eligible for the abortion pill reversal.

The abortion pill reversal consists of the drug progesterone because the woman’s body had stopped producing it naturally when the first abortion pill was taken.This was switched off by taking the first pill of the abortion pill. By not taking the second day's pills and taking the abortion pill stopper as soon as possible (at least within 72 hours) and continuing this until the 14th week of pregnancy, the baby can be saved up to 65% of cases (37).

Women pay a high price for controlling fertility

We are concerned about artificial sex hormones that men use in the gym because of all the effects they have on their bodies. But at the same time, healthy women are routinely prescribed female sex hormones and swallow them for years, despite the increased risk of cancer and thrombosis, sometimes with fatalities and severe emotional disturbances.

Influence on the environment

The hormones in the pill are excreted again and reach the water purification system via the sewer. The sewage treatment system does not succeed in breaking down all the female hormones in the wastewater, causing estrogens to re-enter the environment. Synthetic hormones can be active even at very low concentrations. Estrogens from the pill, for example, are ten times more active than the natural female estrogen (38). Hormone-disrupting effects in the aquatic environment have been clearly and frequently demonstrated. For example, feminization was found to occur in male fish.

What this means for humans and the environment is still unknown (39-43).

No pill, but what else?

There is an alternative to taking the pill. This alternative requires the cooperation of both partners, especially in the field of self-control, but it has no side effects: natural fertility management, also called 'Natural Family Planning' (NFP). NFP is based on the knowledge that, on the one hand, sperm cells only survive in the fallopian tubes for a maximum of five days and, on the other hand, an egg cell can only be fertilized for a few hours. A woman is therefore fertile for a week before ovulation until about a day after it. If one does not have intercourse during this period, pregnancy is impossible. To determine when the fertile period falls, there are several possibilities.

The Billings method makes use of the fact that around ovulation the mucus in the cervix is thinner. It is possible to draw 'threads' from it, as with the white of a raw egg. This is easy to determine yourself. You can even determine when a woman becomes fertile again after a pregnancy.

The sympto-thermal method, such as Sensiplan, is also based on the observations in the cervix mucus, but also uses the woman's body temperature: after ovulation the body temperature rises by about half a degree (five dashes). By taking the temperature daily, one has an extra control on ovulation.

Information about Sensiplan: www.sensiplan.nl

References

1. Council of Europe, Parlementairy Assemblee, Empowering women: promoting access to contraception in Europe. http://assembly.coe.int/nw/xml/XRef/Xref-XML2HTML-EN.asp?fileid=25012&lang=en and https://www.unfpa.org/family-planning
2. The Rights to Contraceptive Information and Services for Women and Adolescents https://www.unfpa.org/resources/rights-contraceptive-information-and-services-women-and-adolescents
3. Wat doen de hypofyse en hypothalamus met je hormoonhuishouding (https://www.cyberpoli.nl/craniofaryngeoom/faq/1333
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