Fertility Problems: Connection to Circadian Rhythm Dysfunction

came across a couple of circadian rhythm studies recently (one just was published this week) that add to the growing body of research that links fertility problems and circadian rhythm dysfunction.

While infertility is a multifactorial problem with involvement of genetics and environmental factors such as xenoestrogens, if circadian rhythm dysfunction is also a factor, this is a foundational aspect that you can greatly impact through a few lifestyle changes.

Quick overview of circadian rhythms: Our body has an internal core molecular clock that is governed by the rise and fall of specific proteins over the course of 24 hours. This core clock is reset by exposing photoreceptors in our retina to light in the blue wavelengths (e.g. getting up in the morning and seeing the sunlight). Circadian examples in your body include the sleep/wake cycle, cortisol rhythm, body temperature dropping at night, and many more.

Human studies for fertility and circadian rhythm disruption are often based on looking at the effects of working the night shift. This can give us the big picture of whether circadian disruption impacts fertility, but it doesn’t always give us the “why”, which can be elucidated through animal studies.

Obviously, we all understand that there is an internal rhythm to ovulation and female hormonal cycles that lasts about 28 days, but the connection to circadian rhythm (24-hour day) may not be initially as clear.

Ovulation is one aspect of fertility that follows a circadian rhythm.  In rats and hamsters, studies show that there is a clear connection to the core circadian clock for the timing of the release of hormones to begin ovulation. This holds true, to some extent, for humans as well. Women have a surge of luteinizing hormone generally in the early morning hours [study].  The timing may be influenced by staying up later at night and have a shifted circadian clock.

Estrogen levels also have a circadian rhythm as well.[study] The researchers collected samples every 2 hours to determine estrogen levels at different points of the menstrual cycle. They found that not only do estrogen levels change over the course of a monthly menstrual cycle, but they also have a daily oscillation pattern as well.

Genetics can tell us a lot as well. We all carry different genetic variants (common mutations) and knowing how those variants affect people can tell researchers a lot about how those genetic pathways affect various conditions such as fertility.

A study in PLOSone earlier this year showed that a couple of genetic variants in one of the core circadian clock genes (called CLOCK) were associated with the risk of spontaneous miscarriages. One of the variants was associated with a doubling of the risk of miscarriage. This is significant in showing that the core circadian clock mechanism is involved in fertility.

Another study in the Dec. 2018 issue of the Journal of Ovarian Research showed that cells surrounding the egg cell in older women had different expression of two circadian rhythm genes (CLOCK and PER) than in younger women. The expression of those genes was about 75% lower in older women (age 39 – 43) than younger (age 24-29). This study was also interesting in that it showed that all of the human core circadian clock genes are active in these ovarian cells.  Gives new meaning to the term ‘biological clock’.

Beyond genetic connection, we can learn a lot from looking at how disrupting circadian function through working the night shift impacts fertility. Studies show that shift work impacts menstrual cycle length and duration as well as changing hormone secretion patterns. Shift work also increases the risk of premature and low birth weight babies.

A study from the 1990s showed that shift work increased the average time it took to conceive. There are quite a few other studies from the ’80s and ’90s pointing to shift work as being hard on women as far as fertility goes. I’m including this not to make anyone feel bad about working the night shift (gotta do what you have to in order make ends meet!), but I wanted to make the point that the information on circadian disruption impacting fertility has been known for more than three decades. Yet it is often overlooked or not discussed.

Let’s switch gears a bit and dig into the recent animal research on circadian rhythm disruption and fertility.

Animal studies give us the clearest pictures of the mechanisms going on genetically because researchers can knock out or alter genes in the animals and then study the effects. Mouse or rat studies are common due to the lifespan and reproductive times for mice being short, relative to humans anyway.

Just last week an animal study was released showing that a mutation in a core circadian clock gene caused a decrease in female fertility as the animals got a little older. This modeled premature ovarian insufficiency (POI), which is a condition that affects about 1% of women under age 40. While POI in humans can be due to rare genetic mutations in the X chromosome or other genes, it also can have a variety of possible causes including the ever-popular ‘unknown origins’. This animal model points to a circadian clock mechanism for POI.

Back to the study details – The core circadian clock genes, PER1 and PER2, are a critical component of the feedback loops that govern our daily rhythms. Without these genes, animal models show a shorter circadian period. PER1 and PER2 levels have been shown to rise and fall daily in ovarian tissue as well as in the pituitary gland, which controls the hormones needed for ovulation. The animal study found that the reason for decreased fertility in animals with mutated PER1 and PER2 genes was premature ovarian insufficiency. In other words, initial fertility was fine, but fertility rates dropped off much more quickly than they should have.

Other studies in mice have shown that knocking out the core clock gene BMAL1 affects fertility. The mice still ovulated, but progesterone was reduced and pregnancy implantation failed.  A second study showed that it was the presence of the BMAL1 gene in the ovary that was necessary for implantation. Researchers found that mice with the BMAL1 gene knocked out were successfully able to reproduce when they had ovaries transplanted from mice carrying normal BMAL1 genes.

How does all of this science stuff apply to women that are trying to conceive?  

The common thread through all of these research studies is the disturbance of the core circadian clock.

You may be thinking, I don’t work the night shift, so none of this applies to me…

Our modern society has created an environment that increases circadian clock disruption in most people. Prior to the invention of the light bulb, our only exposure to light at night was to fire, which is extremely low in the circadian rhythm shifting blue wavelengths. Light at night is now ubiquitous – from watching TV, turning on your overhead lights in your living room, going out into a well lit urban area, playing games on your smartphone.  We have fundamentally changed our core circadian clock through exposure to light at times when our body expects an absence of blue wavelengths.

Another feature of modern society is the propensity to stay up late on the weekends and then sleep in the next morning. Many of us catch a movie on Friday night or go out with friends for dinner and drinks. Why not stay up late when you can sleep in the next morning? Biologically, this is similar to jet lag, where you shift your body’s internal clock by a couple of time zones.  This social jet lag disrupts your circadian clock. We, humans, are resilient, and staying up late once in a while is probably not going to have that much overall impact. But chronically shifting your circadian clock by a couple of hours each weekend, and then shifting back on Monday morning, is having an impact on your long-term health – and also can be impacting your fertility.

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