Levonorgestrel: a renaissance in safety and availability. Marchenko L.A.


Levonorgestrel as a contraceptive

Due to these properties, levonorgestrel is widely used in the production of a variety of contraceptives, both alone and in combination with synthetic estrogen analogues.

Contraceptive drugs that contain exclusively levonorgestrel include:

  • so-called mini-pills, progestin-only birth control pills. They contain microdoses of the hormone and are designed to be taken for a month;
  • emergency contraception (“morning after pills” or “Plan B” pills). The dose of the hormone in them is slightly higher than in the mini-pill, so they can urgently prevent unwanted conception within a few days after unprotected intimate contact. These remedies are most effective within 72 hours after sexual intercourse. To ensure contraceptive action, only 1-2 tablets are enough, depending on the drug.

In addition, in combination with synthetic estrogen analogs, levonorgestrel is included in a variety of combined oral contraceptives, vaginal rings, intrauterine devices, and implants.

Levonorgestrel: a renaissance in safety and availability. Marchenko L.A.

Vera Petrovna Smetnik , professor, doctor of medical sciences:

– I am pleased to give the floor, I would like to ask dear Larisa Andreevna Marchenko, you all know Larisa Andreevna, professor of our department of gynecological endocrinology. The title of the report is very specific: “Levonorgestrel: A Renaissance in Availability and Safety.”

Larisa Andreevna Marchenko , professor:

- Dear Colleagues! It must be said that oral contraceptives are among the most studied and safe drugs in general and hormonal drugs in particular, because we prescribe them for birth control to absolutely healthy women of reproductive age. And today it is clear that 80 million women around the world use these products. Regarding the frequency of use of hormonal therapy, unfortunately, Russia, as always, is in third place, but, unfortunately, from the bottom. And the only good thing is that Japan is behind us - such a highly developed country. Here is a huge number of drugs that are presented on the Russian market, and how can we understand these drugs, what should we prescribe to our patients today. We have figuratively shown all the estrogens and gestagens that are part of oral contraceptives, and you see, microfollin as unnatural, as synthetic ethinyl estradiol, apparently plays the role of a barrier shark, it is most feared, and natural estrogen has already appeared somewhat to the side, which is part of oral contraceptives. And a huge number of different hormonal gestagens that are presented on today's market.

And depending on which gestagen is combined with estrogen, the original drug or a generic drug appears. We know well that hormonal drugs today are used not only for their main indication, protection from unwanted pregnancy, but thanks to the large number of therapeutic effects of progestogens and, above all, progestogens, we have now moved away from a huge number of dysfunctional uterine bleeding. Vera Petrovna will support me; we no longer see such a high percentage of endometrial hyperplastic processes in polycystic ovary syndrome. We do not see the transition of hyperplasia with this pathology to endometrial cancer. We are ideally able to treat patients with dysmenorrhea and premenstrual syndrome. We have entered a new area, we also treat rheumatoid processes, we treat anemia, and these are all the positive therapeutic effects of progestogens, which theoretically would allow us to advance in the oral contraceptive market. And I think that over time, we will move away from this notorious 4-7% use of these drugs in Russia and will move closer to at least Germany, where every third woman receives an oral contraceptive.

But what stops our patients? Side effects of progestogens. And, of course, you understand, there are no drugs that do not have any side effects. And depending on the gestagen that is included in the oral contraceptive, we, of course, saw acne vulgaris at the dawn of oral contraception. And our patients who come, they always have the same order: it is necessary that the drug, the oral contraceptive, does not give them the feeling of engorgement of the mammary glands, so that there is no weight gain, so that there are no headaches. That is, it was necessary to create new and new gestagens that would be devoid of unnecessary glucocorticoid and androgenic properties. And, in general, today this problem has been solved, and the left half of this progestogen tree shows ideal gestagens from the point of view of pharmacologists, which have been created over the past 10-15 years, and we have seen with our own eyes, and you have seen this. And it would seem that gestagens and oral contraceptives have become absolutely safe, and we, in general, have largely forgotten the principles by which we prescribed them. We began to prescribe oral contraceptives to overweight women who smoke; we did not study their medical history in detail. And, naturally, indications began to appear more and more often, especially in the media, about the adverse effects of oral contraceptives. And this, in general, to some extent sometimes led to the fact that our patients began to be afraid of oral contraception. But we must always remember the risk-benefit assessments.

How can we balance on these scales so that our patients have a huge choice of modern drugs, and so that we do not turn away and reconsider the properties of progestin drugs that are included in oral contraceptives? And if we talk about the side effects and risks associated with oral contraceptives, they are negligible. Every young woman, coming to a company and lighting a cigarette, does not think that her risks in terms of some fatal adverse events - lung cancer and death - go beyond this yellow line. She doesn’t think about the fact that she could get into an unfortunate situation where there would be some kind of traffic event, and could die. But why are we so afraid of oral contraceptives? Given that if we follow the rules for prescribing these drugs, we do not prescribe oral contraceptives to women of late reproductive age, smoking and obesity, with metabolic syndrome, why are we afraid of these correct drugs that actually regulate fertility? And we will leave the area of ​​risky abortions, despite the fact that mini-abortions and medical abortions have appeared. And Professor Ginger very well showed the true distribution of risks, the most severe, fatal complications, thromboembolic complications while taking oral contraceptives.

Look at 10 thousand women, how often some kind of thrombotic complication awaits her in everyday life. Almost 2 cases per 10 thousand, and these lower dark risks are not visible. This value doubles for users of modern oral contraceptives, despite the fact that in recent years we have widely introduced oral contraceptives-gestagens, which belong to the third and fourth generation gestagens. They had positive therapeutic effects, an antimineralocorticoid effect, were devoid of glucocorticoid effects, androgenic effects, but thrombosis nevertheless occurred, what was the matter? And look at the risk of thrombosis during an absolutely physiological situation that every woman strives for: pregnancy. The risk of thrombosis increases sharply in this physiological condition. So, today we clearly see that against the background of oral contraceptives, the risk of thrombosis increases by 2 times compared to women who do not use oral contraceptives, while during pregnancy this risk increases by 6 times.

But, again, I don’t want to scare you, I want to emphasize that as a fatal event, this risk is very small in relation to the cohort of women who do not have it, per 10 thousand is considered. But why do these complications still arise, which we try to avoid, because both during pregnancy and while taking oral contraceptives, the pro-anticoagulant link of hemostasis is activated, this is inevitable, the anticoagulant potential decreases, and more attention needs to be paid and remember the concept, resistance to antithrombin III decreases. And it is very important to reduce the level of PAI, reduce TAP1 and other indicators that need to be remembered. And today we say that against the background of oral contraceptives, a certain condition begins to form, which brings a woman, in terms of her hemostasis, closer to carriers of a heterozygous mutation, the Leiden mutation, when there is a mutation in the fifth factor. And this is due to the fact that resistance to activated protein C appears. And we must remember this, especially when we use oral contraceptives, oddly enough, of the third generation, which contain gestagens with special positive therapeutic effects, we enhance this effect and get double knockout.

And therefore, it is very important for women to whom we are trying to prescribe the most favorable, from our point of view, hormonal drugs, be sure to study their anamnesis, and if there is the slightest indication of any unfavorable thrombotic complications in the anamnesis of these patients, be sure to recommend a carrier test for hereditary thrombophilia, first of all. Naturally, it is clear that you will never prescribe oral contraceptives to carriers of the Leiden mutation, but the polymorphism of the PAI gene and the TAP1 polymorphism are important in this situation. Our patients need to remember this, because using the example of homozygous carriage of the Leiden mutation, we see that in this situation the risk of developing thrombosis due to oral contraceptives increases from 6.9 times to 35 times. And it’s clear that these are precisely the fatal troubles that arise in our patients; if we examine them on a case-control basis, we will definitely identify some disturbances in the hemostatic system. And just literally a few days ago we had a consultation, Vera Petrovna and I participated in it, when a patient came to us from neurosurgeons, who, according to absolute indications... She had four ovarian apoplexies, and this situation ended with surgical intervention twice intervention on the ovary. And in this situation, she was prescribed oral contraceptives, against which background headaches and unsteadiness of gait developed.

Unfortunately, the doctors did not pay attention to this, she was taken to neurosurgeons, she was given an MRI and found to have thrombosis of the transverse venous sinus. And when we looked at her after the fact, she had a polymorphism of the PAI gene. Naturally, the drug was immediately discontinued, but the question arose, what to do. There will be apoplexies again, how can we fight these apoplexies, which she had in her anamnesis for the fourth time at the age of 26. This is a difficult question that doctors must address. And, apparently, it is, of course, necessary to refuse to take oral contraceptives in some situations, but this should only be a significant situation. We know today that third-generation oral contraceptives, which contain gestagens, unfortunately increase the risk of thrombosis by 1.7 times compared to the second. And the well-studied levonorgestrel, which was part of gestagens at the dawn of our professional youth, today has proven itself better and better in the clinic. And we are leaning toward these drugs with the safe levonorgestrel in oral contraceptives because, by creating new progestins and new oral contraceptives, we sought to create additional estrogenicity of oral contraceptives in order to obtain a positive effect by increasing the level of sex steroid binding globulin. But unfortunately, it is this additional estrogen that leads to these adverse effects. While levonorgestrel, as a representative of the second generation progestin, has a powerful anti-estrogenic effect, there is no additional estrogenicity, so thrombotic complications are less likely to occur with it.

The slide shows that compared to levonorgestrel, desogestrel certainly has a better effect in terms of reducing free testosterone and an anti-estrogenic effect due to the fact that the level of sex steroid binding globulin sharply increases by 3 times. While this is not the case with levonorgestrel, and therefore the development of thrombotic complications occurs much less frequently with it, because it does not develop increased resistance to activated protein C. Is venous thrombosis a serious situation or not? I must say that somehow there was no such targeted attention to this topic before the reviews of the Scandinavian epidemiologist Lidegaard appeared. But he published a work, a meta-analysis, which analyzed work from 2001 to 2009. And he was the first to direct the medical public to the fact that it was with levonorgestrel drugs that there were 2 times fewer thrombotic events than with our, in general, beloved dosogestrel and gestodene, which we, of course, prescribed more widely, because we thought that these gestagens more secure. And especially such a vivid conflict of interests arose this year in Copenhagen, when there was a powerful discussion between pharmacologists and experts.

Naturally, both patients and doctors, you and I, are unwittingly involved in this conflict, because two such monsters as Lidegaard and Professor Dinger initiated the discussion about what to prescribe, what gestagens are in oral contraceptives today, second or third or fourth generation , what's better. But I must tell you that even the chairman found it difficult to maintain order in the room, because no clear answer was received as a result of this discussion. And that’s why everyone is looking forward to a trip to Lisbon this year in June, somewhere in May, end, June. These two serious researchers, epidemiologists, gave their word that over these six months they will seriously understand this problem, and we will still say that the risk of developing thrombosis with the new generation of gestagens increases. Yes, by the way, speaking about the patient I cited as an example. Unfortunately, these thrombotic complications arose on Zhanina and dienogest, and previously she received Yarina. But I think that all the difficulties of this situation were that the patient clearly complained for a year about dizziness, headaches, unsteadiness of gait, and she was not taken off oral contraceptives, and this unfavorable complication arose. Therefore, today, in many studies, levonorgestrel is considered the gold standard when testing progestogen drugs in terms of the possible development of thrombotic complications. We must remember this and approach this drug...

It’s not for nothing that the lecture is called “Renaissance”, because levonorgestrel has a good progestogenic effect, a fairly good antiandrogenic effect, no one talks about additional androgenic effects on these drugs. It practically does not bind to glucocorticoid receptors; unfortunately, it does not have a powerful antimineralocorticoid effect, and it has a very weak estrogenic effect, but, in general, it is a fairly modern progestin drug. Therefore, in the latest articles from 2012 and 2013, our pragmatic colleagues from Germany show that they are increasingly beginning to prescribe oral contraceptives, which include levonorgestrel, to girls 12-15 years old, because they need the safest drugs in this age period . Apparently, we need to take an example from them too. Again, I emphasize that the myth about androgenization against the background of levonorgestrel has now been dispelled, because much was taken from experimental work that cannot be extrapolated to the female population. The same applies to studies that have shown that there is no weight gain, no headaches, no swelling, no engorgement of the mammary glands on this progestin drug. And additional most important non-contraceptive effects of levonorgestrel.

Now we have on the market Oralcon, a low-dose drug, 30 micrograms of ethinyl estradiol and 150 micrograms of levonorgestrel, which not only has a birth control effect, but today we use it for the pathology of abnormal uterine bleeding, for such pathology as ovulatory dysfunction. And along with the already well-proven drug, the Mirena system, and the drug “Qlaira”, which is recommended for patients with dysfunctional, as it is now more correct to say, abnormal uterine bleeding, “Oralcon” is also widely represented on our market. And despite the fact that this is an unoriginal drug, nevertheless, it has been well tested, we will talk about this, my colleague will present this material at the next lecture. And it is already known that the volume of uterine bleeding on Oralcon is reduced by 2 times, and it gives almost the same effect as tranexamic acid, as a non-hormonal drug, of course, inferior to Mirena, we must say this, but this is a completely different approach to treatment. Therefore, today in Russia, oddly enough, but I am pleased that in 2013, every fifth woman was already using oral contraceptives, which included levonorgestrel, while according to data from 2007, in world practice this Every third woman used the drug.

Therefore, of course, if we look at the practical recommendations of the European Society for Contraception and the Russian Society for Contraception, we must say, yes, thrombotic complications are quite serious complications, but again, I emphasize, rare. But in order to avoid unpleasant situations, it is necessary, of course, to use the medical criteria for the acceptability of drugs, which were developed by both our association for oral contraception and the World Health Organization. Of course, we know that we prescribe taking into account the rise in blood pressure; we never have the right to prescribe oral contraceptives to women who suffer from severe hypertension. And, unfortunately, we control, according to the instructions, pressure rises: high pressure rises - we interrupt. Our patient also, I forgot to say, began to have high blood pressure at the age of 26, 150, she began to notice transient hypertension, but still, since she had headaches, this should have alerted the doctors and, of course, she should have stopped taking the medications earlier and examine it for hereditary thrombophilias. This is the main thing I wanted to say.

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