Does discovery of 'severe PMS genes' offer hope of a cure?

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Behind the Headlines

Wednesday January 4 2017

It's estimated around 1 in 20 women have PMDD

"Women who suffer from severe mood swings before their period have a different genetic make-up," The Sun reports.
New research has found a link between a gene complex called ESC/E(Z) and severe symptoms of premenstrual syndrome, known as premenstrual dysphoric disorder (PMDD).
Nearly all women of childbearing age have some premenstrual symptoms – often referred to as PMS or PMT.
But PMDD only affects around 1 in 20 women, and its symptoms – such as depression and extreme anxiety – can be severe enough to disrupt day-to-day life. Many women with PMDD need medication to help.
Scientists found cells from women with PMDD respond differently to the hormones oestrogen and progesterone than cells from other women.
They identified differences in the genes expressed in the cells, both before and after they were exposed to the hormones.
Although the researchers say a particular group of genes called ESC/E(Z) complex were involved, they don't know exactly how this affects PMDD symptoms.
They say this is the first time scientists have shown a difference between women with and without PMDD at a cellular level. This suggests the condition might have an inherited basis.
But they stress that we need to be cautious about the biological relevance of these findings.
Any treatments that target hormonal responses run the possibility of triggering a wide range of side effects.
So a realistic answer to the question in our headline? "A cure is probably a long way off."

When to seek help with premenstrual symptoms

The symptoms of PMDD are similar to those of PMS, but are more exaggerated and often more psychological.
Symptoms can include:

• feelings of hopelessness
• persistent sadness or depression
• extreme anger and anxiety
• sleeping much more or less than usual
• extreme tension and irritability

See your GP if you regularly experience any of these symptoms before your period. There is a wide range of treatment options.

Where did the story come from?

The study was carried out by researchers from the US National Institutes of Health and the University of North Carolina, and was funded by the National Institutes of Health. 
It was published in the peer-reviewed journal, Molecular Psychiatry.
This is a complex story and some media sources handled it better than others. The Independent gave a good overview.
Both The Daily Telegraph and the Daily Mail confused premenstrual dysphoric disease (PMDD), a severe form of PMS, with the outdated term premenstrual tension (PMT), both saying that scientists have discovered an explanation for why some women get PMT.
They also overstated the significance of the findings, which the researchers themselves said need to be confirmed and investigated further.

What kind of research was this?

The researchers began with a case-control study to identify how women with and without diagnosed PMDD responded to hormones.
They then took blood from the women to grow cultures of white blood cells, which they genetically sequenced before and after exposure to hormones.
Case-control studies can point to differences between groups (in this case, women) but can't explain what causes them.
Experiments on cells can point to interesting avenues for further research, but in isolation they don't show us how the cells interact with the body as a whole.
The researchers used blood cells, but we don't know whether cells in the brain and nervous system, for example, would react in the same way.

What did the research involve?

Researchers recruited 34 women with and 33 women without PMDD.
A small number from each group (10 with and 9 without PMDD) took part in a six-month study where they were given sex hormone blockers (drugs that reduce the effect of sex hormones) to see what effect it had on their moods. The blockers were then discontinued.
This was to confirm that the sex hormones in question – oestrogen and progesterone – had little effect on women without PMDD, but a big effect on symptoms of women with PMDD.
The researchers then took blood samples from all the women, cultured their white blood cells and used ribonucleic acid (RNA) sequencing to look at how the cells responded to hormones.
They first checked that white blood cells expressed the sex receptor genes necessary to respond to oestrogen and progesterone.
Then they sequenced messenger RNA (mRNA) from the cells to look for differences between that of women with and without PMDD. mRNA carries messages from the DNA in the cell nucleus to the cell, where proteins are formed.
They repeated the sequencing in cells that had been exposed to oestrogen and progesterone for 24 hours.
The researchers then focused on differences found in the ESC/E(Z) complex of genes, as previous research had shown this might play a role in hormone-related mood disorders.
They looked at which genes were switched on and off, how this differed between cells from women with and without PMDD, and what effect this had on protein formation.

What were the basic results?

The researchers found:

• Women with PMDD had improved symptoms while taking a hormone blocker (the gonadotrophin-releasing hormone receptor agonist leuprolide), but their symptoms returned when given oestrogen or progesterone.
• More genes from the ESC/E(Z) complex were "switched on" in cells from women with PMDD, but the genes were less likely to prompt the formation of proteins.
• When the researchers added oestrogen and progesterone to the cells, some genes were switched on in women with PMDD that were switched off in women without, and vice versa.

How did the researchers interpret the results?

The researchers said: "We think that the cellular difference we found captures an important component of vulnerability to PMDD", but warned that there are "many important elements" in the nervous system that cannot be seen in the blood cells.
They say that the "biological relevance" of their findings "should be interpreted cautiously" until future studies have outlined more clearly the role of the ESC/E(Z) complex genes in PMDD.

Conclusion

PMDD can make life extremely difficult. While hormone treatments and antidepressants help some women, you can't use hormone treatments if you're trying to get pregnant, and they have side effects that mean they're not suitable for everyone.
Finding out more about the condition is a first step to understanding it, and might lead to better treatments in the long term.
This early-stage research shows that the genetic make-up and response cells have to hormones may have a hand in how likely women are to get PMDD.
But we're a long way from knowing for sure if these cell responses are actually a cause of PMDD.
It's possible that the differences seen by the researchers might be the result of reverse causality – in other words, having a long-term mood disorder has shaped how the cells respond to hormones, rather than the other way around.
The groups in this study were not matched in terms of previous history of a major depressive episode, which had occurred in a quarter of women with PMDD.
And as this was not a randomised controlled trial, there may have been other unmeasured differences between the two groups that could account for the differences seen.
Because the researchers only looked at a small number of women with PMDD, we don't know if this research has any relevance to the much more common premenstrual syndrome (PMS), which includes symptoms of irritability, breast tenderness, mood swings and bloating.
The researchers say "it would only be a matter of speculation" to suggest these findings could apply to PMS.
If you have premenstrual symptoms that are making everyday life difficult, see your GP. Lots of treatments are available.
Read more about treatments for premenstrual symptoms.