IMMDS Review listens to Professor Neil Vargesson about Primodos Studies

Independent Medicines and Medical Devices Safety Review Oral Hearing, 27th November 2018

The Independent Medicines and Medical Devices Safety Review is Chaired by Baroness Julia Cumberlege CBE DL.

In February 2018, the Secretary of State for Health and Social Care, the Rt Hon Jeremy Hunt MP, announced a review into how the health system responds to reports from patients about harmful side effects from medicines and medical devices. The announcement in the House of Commons follows patient-led campaigns on the use of the hormone pregnancy test Primodos, anti-epileptic drug sodium valproate and surgical mesh.

About Primodos

  • Read and/or download the full study (free access) Oral hormone pregnancy tests and the risks of congenital malformations: a systematic review and meta-analysis, F1000Research, First published 31 Oct 2018, 7:1725, DOI:10.12688/f1000research.16758.1.
  • Read and/or download the full study (free access) The Primodos components Norethisterone acetate and Ethinyl estradiol induce developmental abnormalities in zebrafsh embryos, nature, Published 13 Feb 2018, DOI:10.1038/s41598-018-21318-9.
  • To read some real stories told by the Primodos victims, go to this post comment section.  Read our posts tagged primodos.

Controversial pregnancy test drug shows deformities in zebrafish embryos within hours of exposure

Primodos drug components can cause embryonic damage in a dose and time responsive manner

“This is a great stepping stone. It doesn’t give definitive answers, but it’s a start, so we can finally put to rest whether or not Primodos caused birth defects

Dr Vargesson says.

The components of a controversial drug, allegedly linked to birth defects in the 1960s and ’70s, caused deformations to fish embryos just hours after they received a dose in new studies by researchers at the University of Aberdeen.

Primodos was a hormone pregnancy test used by thousands of women in the UK between 1958 and 1978.

“The first step was to show the drug has caused problems in fish and hopefully that will lead to some funding for tests on mammals and other tissues to show exactly what is going on.”

Dr Vargesson says.

Research at the time suggested the drug could be linked to a higher risk of women giving birth to babies with abnormalities – a claim denied by Primodos’ manufacturer.

Although Primodos is no longer in use, its components (Norethisterone acetate and Ethinyl estradiol) are used in other medications today including treatments for endometriosis and contraceptives.

“This research helps the campaigners because they can see there has been some up-to-date science being done with modern techniques.”

Dr Vargesson says.

In November last year a UK Government expert working group (EWG) study found no ‘causal association’ between the drug and the abnormalities, stating that outdated methods used by scientists in the 1970s was partly responsible for a failure to find a connection.

Now a new study at the University of Aberdeen, published today in the Scientific Reports journal, has revealed more about the effects of Primodos’ components on the embryos of zebrafish

The paper outlines how after the components of Primodos were added to water around zebrafish embryos, their movement slowed down rapidly; developed changes to the heart within four hours; and within 24 hours displayed damage to tissues such as the fins, eyes and spinal cords.

“I would like to think the PM will take this on board and consider there might be an alternative decision to the one the Commission On Human Medicines made in the Westminster report.”

Dr Vargesson says.

More surprisingly, according to the researchers, the study showed that the drug accumulates in the zebrafish embryo over time. They suggest that if this also occurs in a mammalian species that even a seemingly low dose of the drug for the mother could result in much higher levels for the embryo.

This latest study was led by Dr Neil Vargesson from the University of Aberdeen, who has also published extensive research into thalidomide – a drug used in Germany in the 1950s to treat morning sickness but which caused thousands of babies worldwide to be born with malformed limbs.

“At the moment the scientific research into whether or not Primodos caused these birth defects is inconclusive.”

“What this study highlights is that there is a lot still to be learned about Primodos and more widely its components effects on mammals.”

“Our experiments with the zebrafish embryos shows quite clearly the effects the Primodos components have. This does not mean it would do the same in humans of course, we are a long way from saying that but we need to carry out more research into these components because they are still in drugs today and in some cases in much higher doses than those found in Primodos.”

“The assumption by some previously has been that the doses given to mothers was too low to cause any damage but our study shows that the levels of Primodos’ components accumulate in the embryos over time because they don’t have a fully functional liver that can break down the drug. This too is new information and if the same thing happens in mammals, these drugs could build up in the embryo to much higher levels than shown in the mother’s blood.”

Dr Vargesson explains.

More About Primodos

Primodos Link to Embryo Damage – SkyNews Report

Hormone Pregnancy Test Drug Given to 1.5M Linked to Birth Defects, New Study

The Primodos components Norethisterone acetate and Ethinyl estradiol induce developmental abnormalities in zebrafish embryos“, a newly published research produced by Dr Neil Vargesson from the Institute of Medical Sciences in Aberdeen University, shows that Primodos (hormone pregnancy test) drugs had the potential to deform embryos in the womb.

More About Primodos

Primodos drug components can cause embryonic damage in a dose and time responsive manner

The Primodos components Norethisterone acetate and Ethinyl estradiol induce developmental abnormalities in zebrafish embryos

2018 Study Abstract

Primodos was a hormone pregnancy test used between 1958–1978 that has been implicated with causing a range of birth defects ever since. Though Primodos is no longer used, it’s components, Norethisterone acetate and Ethinyl estradiol, are used in other medications today including treatments for endometriosis and contraceptives. However, whether Primodos caused birth defects or not remains controversial, and has been little investigated.

Here we used the developing zebrafish embryo, a human cell-line and mouse retinal explants to investigate the actions of the components of Primodos upon embryonic and tissue development.

We show that Norethisterone acetate and Ethinyl estradiol cause embryonic damage in a dose and time responsive manner. The damage occurs rapidly after drug exposure, affecting multiple organ systems. Moreover, we found that the Norethisterone acetate and Ethinyl estradiol mixture can affect nerve outgrowth and blood vessel patterning directly and accumulates in the forming embryo for at least 24 hrs.

These data demonstrate that Norethisterone acetate and Ethinyl estradiol are potentially teratogenic, depending on dose and embryonic stage of development in the zebrafish. Further work in mammalian model species are now required to build on these findings and determine if placental embryos also are affected by synthetic sex hormones and their mechanisms of action. Image credit nature.

More About Primodos

More evidence about Duogynon dramatic side effects

A Scottish biologist examines the damaging effects of the Duogynon pregnancy drug

They were born with an open back, with heart defects and brain damage, shortened or missing limbs, deformed intestines, bladders or genitals. The cause for the malformations, among which hundreds of Germans and Britons born between the beginning of the 1950s and the middle of the 1970s, still today as adults, is given to a former drug of the Berlin pharmacy company Schering.

Mothers had received a drug from their doctors at the beginning of their pregnancy to determine if they really expected a child : named Duogynon in Germany, Primodos in the UK. Their content, a combination based on the female sex hormones gestagen and estrogen, was the same ; it could be swallowed or injected and was able to cause a menstrual bleeding.

If menstruation did not take place despite the hormone shock, the woman was considered pregnant. Urine test strips had not yet prevailed.

For the first time, the serious suspicions that are on the preparations of the past could be systematically examined by independent experts and at the present state of science. Neil Vargesson, professor of biology at the Scottish University of Aberdeen, researched on embryonic malformations for many years. He has worked with a team of his faculty to reproduce the Duogynon, Primodos, active ingredient and has already been tested in the laboratory for zebrafish embryos for its fruit-damaging effects.

“We were able to demonstrate that Primodos actually damages fish embryos, depending on both the stage of embryonic development and its dosage.”

Vargesson told the taz.

The Missing Proof

So far there have been indications, but no evidence for a causal link between the intake of Duogynon and the malformations. On the one reason being that clinical studies from the 1950s – when Schering brought the drug on the market – were not carried out in a way from which evidence could be derived. Another reason being that Duogynon has not been produced anymore for almost 40 years. Schering was taken over by Bayer AG in 2006, and they categorically excludes Duogynonas the cause of embryonic malformations“.

“The exact mechanism of action of Primodos / Duogynon on zebrafish is not yet known, but there are indications that the developmental stage of the blood vessels and the nerves play a key role in the nature and extent of embryonic damage”

said Vargesson.

“We could see enlarged hearts, open backs, damaged blood cells and damage to the nervous system. It is not just premature, but dubious, from these first results, to draw conclusions about possible damage to human embryos, I estimate that we will have to research at least three to five years in the lab and in very different animals”

said the scientist.

“Zebrafish, whose embryonic development is similar to those of higher vertebrate animals, and which develop completely and very quickly outside the mother’s body, are an important model organism for biologists. However, further experiments on rodents, fish and also sheep are essential in order to make assured statements. Research on pregnant women is prohibited for ethical reasons”

Vargesson said.

“You have to emphasize again and again that there is no such a thing as a natural malformation rate. Three per cent of all newborns are born with malformations, without apparent causes.”

added Vargesson.

New Hopes

The research approach of Neil Vargesson brings nevertheless new, great hope for the alleged Duogynon victims who have so far vainly struggled in the United Kingdom and in Germany as self-help groups for the recognition of their suffering by governments and parliaments and for a compensation fund based on the model of the foundation for contergan victims. Whether and how fast reliable results will be available, however, is also a matter of financing. The British parliament, which has been examining medical and scientific findings on Duogynon for one and a half years, has recently invited the Scottish biologists to a meeting. There were no concrete financial commitments so far.

“It’s also unusual to want to research a drug that is not there. My attention for Duogynon, came about by chance, almost as a by-product of my actual research interest.”

admited Vargesson.

Contergan was recommended to pregnant women in the 1960s against morning sickness and triggered one of the biggest drug scandal of the past century. The question of how the drug, can be used without harming unborns in the mother’s womb has been the focus for many years. Contergan is still of great therapeutic interest and use, said Vargesson, for the treatment of leprosy as well as certain types of cancer of the plasmatic cells.

Contergan Open Questions

​​Despite years of intensive research, it is still unclear as what exact building blocks of Contergan drug cause the malformations.

Vargesson does research on this, since he wants to know which molecules he has to forego completely, which he could change as well as which he should exchange, in order to make the medium safe and yet medically usable. Vargesson has recently patented several promising varieties of a slightly modified conteric.

Vargesson is optimistic:

“When I heard that another drug might also cause malformations in unborn babies, I had to look at the matter more closely.
Certain substances that were present in Duogynon are still found today in modified form in antibabies. There should be an interest in exploring possible undesirable side effects.
Whether it goes, and how, will depend above all on financial decisions.”

  • Original press release : FEHLBILDUNGEN DURCH DUOGYNON, on taz, 2.6.2017.
  • Translation via Google.
  • Image credit taz.