The Rhythm is Gonna Get You

Are you a morning person, no? Me neither. We all tend to have a rhythm to our days that we prefer; some of us prefer to go to bed at 9pm, some us at 2am. Your preference for patterns of waking and sleeping actually has a biological basis called the circadian clock. This is, essentially, your body’s internal clock (which is essentially the timed switching on and off of certain genes) and allows your body to anticipate events that happen repeatedly every day and produce the correct physiological response (like feeling sleepy or awake at certain times).   Our circadian clocks are controlled by a small part of the brain called the suprachiasmatic nucleus (SCN) located within the hypothalamus. The SCN is responsible for coordinating rhythms in the hypothalamus and the pituitary gland which in turn form part of the hypothalamatic-pituitary-gonadal (HPG) axis. This HPG axis is important for driving the rhythms of several organs in your body, but most importantly for the subject of this week’s blog post, it orchestrates the rhythms in the reproductive organs.

In women the regulation and rhythm of the menstrual cycle is a tightly controlled systems involving the HPG axis. Below is a diagram that summarises how the components all work together.

Interestingly several organs in the human body have their own distinct clock (called a peripheral clock) that are linked to the clock in the brain (the central clock). One such peripheral clock is in the ovaries. The ovaries, in concert with the brain, control the monthly variation in hormonal levels and the menstrual cycle. However, not only do levels of hormones change over the month, but also over the course of a day. A good example of this is that the monthly LH surge, mentioned above, requires a certain signal at the end of a resting period, which is why 80% of women have their LH surge around 8 a.m.  However, it is not fully understood (in humans at least) how the monthly and daily variations in hormone levels are regulated.

Altering the pattern of exposure to light, food and sleep can disrupt the body’s clock which can have negative effects ranging from feeling sluggish to serious illnesses (in the case of long term disruption). Disturbances in the normal cycle of waking/sleeping/eating etc have been suggested to cause alterations in hormone levels. Indeed some studies have shown that even partial sleep deprivation can lead to temporary increases in estrogen and luteinizing hormone, as well as altering the production of several other hormones. Another study showed that women with certain mutations in a gene that is turned on in an area of the brain that controls circadian rhythms leads to those women experiencing more miscarriages and less pregnancies than those women without the mutation. So clearly there is an important link between cycles in the brain and the reproductive system and disrupting one can adversely affect the other.

As modern society creates the necessity for longer and more varied working hours it is inevitable that some people will work at times that are out of synch with the ‘normal’ waking/sleeping rhythms we are used to. Disruption of the normal patterns of sleep because of shift working has been suggested to increase the risk of conditions such as cardiovascular disorders, gastrointestinal disorders, cancer and mental health conditions. So clearly there are negative health effects associated with shift work.

Of particular interest then are studies that have suggested that night shift work can increase the risk of having endometriosis, in some cases by as much as 50%. This same study found that there were no associations between endometriosis and mutations involving genes that regulate circadian rhythms, which leads me to believe the increase in risk was due to changes in hormones as a direct result of shift work. Now before I go any further there is a question I would like you to consider. Does night shift work actually increase the risk of developing endometriosis, or does night shift work increase the severity of endometriosis related symptoms making it more likely to be diagnosed? I very much doubt that night shift work can actually cause endometriosis, but it is certainly feasible that disruption of hormonal cycles by shift working could worsen the symptoms.

Indeed some studies have shown that, while levels of FSH and LH are not affected by night shift work, levels of estrogen are significantly increased, possibly due to a lengthening of the follicular phase of the menstrual cycle. Additionally melatonin, a hormone whose production is greatly affected by light/dark cycles but also has anti-estrogenic effects, has been shown to be reduced in shift workers. Perhaps as a result of this further studies demonstrated that shift work can cause alterations to menstrual cycle length and regularity.

Is there any way we can tie these effects to the symptoms of endometriosis? We know that when it comes to endometriosis, heightened levels of estrogen are bad. Pretty much all medical therapies for endo are based on reducing estrogen levels. Estrogen leads to increased growth and inflammatory action of endometriotic lesions.  Estrogen also increases the production of enzymes that produce chemical messengers called prostaglandins. Prostaglandins have several different functions, but in the uterus, they control the contractions of the uterine muscle, which are more commonly known as menstrual cramps. Excessive prostaglandin production can lead to severe and debilitating menstrual cramps (dysmenorrhoea) which is the most common symptom experienced by women with endometriosis.Therefore it could be that increased estrogen levels as a result of shift work could increase the severity of endometriosis associated dysmenorrhea.

I mentioned melatonin before as well and that was no mistake. There has been a lot of interest recently in melatonin as a treatment for endometriosis associated pain. Whilst most of the studies have only been lab based so far, some clinical trial data suggests that melatonin therapy could reduce the chronic pain associated with endometriosis as well as improve sleep quality.

In some ways the symptoms of endometriosis may be forming a vicious cycle. Some studies have shown that a substantial proportion of women with endo (of the cul-de-sac in the case of this study) experience sleep disturbances, insomnia and daytime fatigue. 

This goes a way to show how treating endometriosis should be viewed from many different angles to achieve maximum effectiveness. At present most medical therapies for endo are focussed on one particular aspect of the disease. A broader view of the disease and all of its strengths and weaknesses are needed before sufferers really see some benefit. 

Report from Juneau Biosciences

Way back in the distant and hazy past of 2009 I wrote about a company called Juneau Biosciences who were looking to recruit women with endometriosis for genetic research study. Well the results are in and they have released a preliminary report on what they have found.

The report states that they have found mutations in an imprinted gene called NLRP2 that are more common in women with endometriosis. What does this mean? Well, that will be the subject of todays blogpost.

First of all we need to understand what an imprinted gene is and why they are important. I’ve wrote before about genes, what they are and how they work, but what are imprinted genes? Normally a child inherits two ‘active’ copies of each gene, one from the mother and one from the father. However in some cases one of the genes, from either the father or the mother, can be switched off or ‘imprinted’ meaning that the child only has one working copy of the gene. This makes imprinted genes more ‘vulnerable’ because normally there would be two working copies of each gene, so if one copy gets mutated or stops working, there is a backup copy. With imprinted genes there is no backup, so if that gene has an important function (like preventing a cell becoming cancerous, for example) then there is a greater risk of a deleterious effect occurring.

Onto the next question, what does NLRP2 gene do and why is that relevant to endometriosis? The products of NLRP genes, in general, have a role in regulating the immune system and inflammation, which may be their most relevant known function in endometriosis. In particular NLRP2 has been shown to inhibit some key mediators of inflammation. Endometriosis is characterised by an increase in inflammation, both around the lesions and throughout the whole body (it is even thought that this might contribute to the fatigue many women with endometriosis experience). Also, I have written previously about how women with endo are at a higher risk of certain inflammatory and immune conditions, like inflammatory bowel disease, allergies and asthma to name a few. So finding alterations in a gene that is involved in inflammation and the immune system is potentially quite intriguing.

It could be tempting to suggest that this new finding could go some way to explaining why there is excess inflammation in endometriosis. However the sheer number of factors that contribute to the regulation of inflammation in endometriosis is huge (and still not fully understood) so exactly how significant a single factor is remains to be seen (in any case, the exact role of NLRP2 in general has been poorly characterised). Another point is that we need to know how these mutations in the NLRP2 gene affect the function of the protein it produces.

So there is a way still to go before this research can be translated into something relevant for the women living with endometriosis, but all progress needs a starting point, and this is a pretty good starting point.