Second and third generation contraceptive pills

This article focuses on the different generations of the combined pill, why they were developed and the differences between them.

Introduction

The first contraceptive pill was developed in the 1960s, and since then a lot has happened. There are now around 40 different pill brands, all of which work in the same way as the original pill, but contain different combinations of hormones.

In addition to the combined pill, hormonal contraception can be used as a skin patch (Evra) and vaginal ring (Nuvaring).

Why develop different generations of the pill?

There are two reasons for developing so many different pills:

  1. To try to improve patient safety on the pill
  2. To minimise pill side effects.

Over time, as new pill formulations were developed, newer hormones were incorporated. Initially this was by changing the progesterone constituent of the pill to a more modern type, but more recently, combined pills have been developed with newer estrogens too.

These groups of pills were divided into classes - as first, second, third, and now fourth, generation pills – according to their hormonal content.

List of first, second, third, and fourth generation pills

  • First generation pills contained the estrogen mestranol. They also contained the progesterones norethindrone, or norethnodrel. These are no longer in general use.
  • Second generation pills contain the estrogen ethinyl estradiol. They also contain the progesterones levonorgestrel (Microgynon 30), or norethisterone (Loestrin 30).
  • Third generation pills contain the estrogen ethinyl estradiol. They also contain the progesterones desogestrel (Marvelon), or gestodene (Femodene).
  • Fourth generation pills contain either the same estrogen ethinyl estradiol, plus a new progesterone drospirenone (Yasmin), or a different estrogen 17 B estradiol (a natural estrogen) with nomegestrol acetate (Zoely), or estradiol valerate (a natural estrogen) and dienogest (Qlaira).

Pills from all four generations work the same way, and are all very similar in terms of efficacy to stop women becoming pregnant.

The pill and thrombosis

Soon after the pill was first marketed, there were reports linking the pill to deep vein thrombosis. This is a medical condition in which blood clots form spontaneously in the deep veins of the legs (deep vein thrombosis) or in the lungs (pulmonary embolus).

Thrombosis is a serious medical condition, which although treatable, may occasionally be fatal.

Why should the pill cause thrombosis?

There are two hormones in the pill – estrogen and progesterone. The estrogen in the majority of pills has (almost always) been a synthetic estrogen called ethinyl estradiol (EE). The progesterone component was specifically changed between brands. However, fourth generation pills nowadays do contain new, natural estrogens.

Ethinyl estradiol stimulates blood clotting factors, predisposing users to develop a clot. The progesterone in the combined pill however is important, because this clotting effect is modified by the particular type of progesterone. Second generation pills (levonorgestrel and norethisterone) seem to counteract this effect better than third generation pills (desogestrel and gestodene), and hence have a slightly lowered risk of thrombosis. The difference however is very small.

It's now over 50 years since the first pills were prescribed in the UK, meaning there is wealth of clinical experience with its use. The clinical debate about which pills cause the highest or lowest risk of thrombosis is ever present, but the current consensus of opinion is presented below.

What is the risk of a thrombosis on the combined pill?

The Faculty of Sexual and Reproductive Healthcare (FSRH) summarised the current evidence about the risk of thrombosis and use of hormonal contraception in a 2016 statement.

The Faculty underlined the numerous advantages and benefits of taking combined hormonal contraception. This now includes not only the pill, but also the contraceptive patch (Evra) and the vaginal ring (Nuvaring).

The benefits and risks should be clearly weighed up for an individual before prescribing any contraception. Women wishing to take the combined pill, the patch or the vaginal ring, should be informed about the small increase risk of a thrombosis associated with the use of these products.

The risk of thrombosis in women using the combined pill, patch or ring is set out in Table 1 below.

Table 1: Risk of thrombosis in women using combined hormonal contraception, while pregnant and after giving birth
MethodRisk of thrombosis
Non user2 per 10,000 women per year
Second generation pills e.g. Microgynon 30 (levonorgestrel) and Loestrin 30 (norethisterone).5-7 per 10,000 women per year
Third generation pills e.g. desogestrel (Marvelon), gestodene (Femodene) or drospirenone (Yasmin), norelgestromin (Evra) and etonogestrel (Nuvaring).6-12 per 10,000 women per year
Pregnancy29 per 10,000
After delivery300-400 per 10,000

From Table 1, you can see that you are far more likely to have a blood clot in pregnancy or after having a baby, than you are on the pill.

In addition, the chance of dying if you have a thrombosis is less than 1%.

To keep it simple, in terms of thrombosis, it seems that the third generation pills may have a slightly higher risk of thrombosis than the second generation pills, but the difference in risk is small. So long as you accept the risk at 6-12 per 10,000 users, you can use any combined pill you like. This risk is still less than the risk of thrombosis in pregnancy and after childbirth.

To stay healthy on the pill, it's important to keep your risk factors for thrombosis as low as possible.

What are the advantages of the newer generation pills?

Possibly less side effects? Around 30% of women discontinue their pills within the first 3 months, apparently because of side effects (study data). Third generation pills may be associated with less in the way of some side effects. Because the progesterones desogestrel and gestodene are less androgenic (male-type), using these types of pills may have less in the way of androgenic side effects (study data) e.g. mood swings, acne, bloating, and PMT type symptoms. However, bleeding patterns have not been shown to be any different.

How common are side effects on the pill really? Interestingly, side effects due directly to taking the pill, may not be as common as they are made out to be. It is important to note that in some studies using combined pills and placebo (dummy) pills, where neither the investigator nor the study participant knew what they were taking, there were similar numbers of side effects in the group taking the placebo pills.

Non-contraceptive benefits - one of the reasons for taking the pill may be to obtain non-contraceptive benefits such as improved acne, less mood swings, bloating, and PMT. The combined pill reduces painful, heavy periods. It is also a good treatment for women with polycystic ovarian syndrome.

The anti-androgenic effect of third and fourth generation pills may be very helpful to treat a lot of these symptoms, for example, at improving acne. Specific pills used to treat acne are Yasmin (drospirenone), and a similar alternative is Dianette (cyproterone acetate). (There are specific recommendations for using Dianette which are beyond the scope of this text. If you want to take Dianette you must discuss this with your doctor.)

No clear association with weight gain - there is no clear evidence that taking any of the pills, causes weight gain. This is often disbelieved, but medical research has shown that women gain weight as they age, whether they use a hormonal method of contraception, or a copper IUD (plastic and copper - no hormones).

If you are convinced you have put on weight on the pill, the lower dose pills such as Mercilon (desogestrel) or Femodette (gestodene) may seem a logical choice. These contain 30% less estrogen, but they are just as effective as a contraceptive.

Why a fourth generation pill? The fourth generation pills have been developed containing natural estrogen in the hope they may prove safer with long term use. There is not yet enough clinical evidence to substantiate this but they are often used by women who prefer 'natural' hormones, or who have had estrogenic side effects on other pills (nausea, vomiting, breast tenderness). They are a good solution if you have tried various other pills and not got on well with them.

In summary

In summary: third generation pills seem to have a slightly higher risk of thrombosis than second generation pills, but the difference is very small. The benefits and advantages of taking the combined pill should not be overlooked. It is important to find a pill which suits you, which you can continue to take happily and from which you can benefit from excellent contraceptive cover and without an unplanned pregnancy.

Overall, the ball park risk of a thrombosis on the combined pill is in keeping with that of the third generation pills: 6-12 in 10,000 per year of use. In fact, the other second generation pills have a thrombosis risk which is slightly lower.

If you accept the third generation pill risk as above, so long as you are medically eligible, you are able to use any combined pill you choose.

The user must be the chooser!

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Authored 06 November 2018
by Dr Tony Steele

Last updated 26 November 2018


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