Hot of the presses we have an excellent review paper looking at circadian disruption as a cause of infertility. There are some excellent takeaways from this paper and they lay out the science nicely.

Firstly, the authors lay out how circadian rhythms regulate hormones that dictate reproductive success. Second, they look at circadian disruption in animal models of male and female infertility. Finally, they look at the way genetic mutations in clock genes affect human fertility.

Let’s break this down point by point

Reproductive hormones and circadian rhythms

Circadian rhythms regulate all sorts of hormonal outputs, including reproductive hormones. As a result, circadian disruption impairs the tightly regulated process of reproduction.

The authors lay forth a pretty strong argument.

It is interesting to note that the regulation of the estrus cycle, luteinizing hormone (LH) surge, sperm production and maturation, and the timing of insemination and fertilization are regulated by clock genes [6,8].

In men, testosterone and other androgens follow a circadian rhythm with a peak in the morning. Most female sex hormones follow a circadian rhythm dependent on the phase of the cycle as well.

FSH, LH, estrogen, SHBG, and progresterone follow a circadian rhythm during the follicular phase. During the luteal phase, only FSH and SHBG follow a circadian rhythm. Moreover, clock genes regulate the activity of estrogen receptor alpha, regulating tissue sensitivity to estrogens.

But it’s not simply a one-way street. While circadian rhythms regulate output of reproductive hormones, reproductive hormones also regulate circadian rhythms. As a result, circadian disruption can be the cause of infertility, or it can be an effect of it as well.

Regulation of fertility by cortisol and melatonin

Cortisol is a hormone secreted by the adrenal glands that follows a strong circadian rhythm. Furthermore, cortisol acts to synchronize peripheral clocks to the master clock.

The cortisol rhythm is essential to reproductive success, and excessive cortisol production can impair many steps of reproductive fitness including:

• Impairing stimulation of sex hormone release
• Decreasing the synthesis of sex hormones in the pituitary
• Inhibiting local synthesis of sex hormones in the testis and ovaries
• Decreasing embryo implantation rate via damage to the uterus
• Damaging the ovaries
• Decreasing egg quality

As a result, men with excessively high cortisol produce fewer sperm of lower quality. Women experience abnormal cycles or have problems getting pregnant or maintaining a pregnancy. It’s important to point out that stress increases cortisol production, and exposure to high levels of stress or stress at the wrong time can have the same effect.

Another circadian hormone regulated by the master clock with an impact on fertility is melatonin. There are melatonin receptors on both egg and sperm. Further, low melatonin associates with lower sperm quality and in women with fertility of unknown origin.

In sperm, melatonin acts as an antioxidant, protecting it from oxidative damage. In women, higher melatonin levels associate with a higher follicle count. And in the fetus, melatonin helps protect against metabolic stress and helps set the fetal circadian clock.

To sum up, both melatonin and cortisol are important circadian hormones that impact fertility. A proper circadian rhythm for both is essential to reproductive success.

Disruption in circadian genes as a cause of infertility

In different mouse models of circadian disruption, knocking out core clock genes leads to impaired motility in both male and female mice. Knocking out clock genes disrupts sex hormone balance, lowering progesterone and luteinizing hormone(LH) levels in female mice.

In male mice, knocking out clock genes lowers testosterone and causes them to become infertile. For both male and female mice, knocking out the core clock gene Bmal1 impairs the conversion of cholesterol to pregnenolone.

Being the first step in steroid hormone synthesis, this affects the reproductive organs AND adrenals. The microbiome also plays a role as it regulates circadian rhythms and vice versa. In fact, proper sexual development is dependent on an intact microbiome and its interaction with xenobiotic receptors in the gut.

In humans, shiftwork is associated with a longer time to achieve pregnancy:

…the sleep and inherent circadian rhythm disturbances of shift work could lead to menstrual irregularities due to altered levels of FSH, LH and prolactin.

Further, expression of Bmal1 is lower in the endometrial tissue of women with recurrent miscarriage. A polymorphism in Bmal1(rs2278TT749 TT) is associated with a greater number of miscarriages AND pregnancies.

The CLOCK gene also plays a role in successful conception. The placenta functions as a peripheral clock, and CLOCK expression levels are higher in the healthy fetus than a spontaneous miscarriage. Polymorphisms in CLOCK also play a role in lower sperm count and quality in males.

Conclusion

Rates of infertility are currently on the rise. Approximately 13 out of 100 couples have difficulty conceiving a child, taking more than 12 months to conceive.

Male and female infertility account equally for the declining rate. For couples who have difficulty conceiving, 1/3 of the time it’s due to female issues, 1/3 of the time it’s due to male issues, and 1/3 of the time it’s a combination.

Reproductive success comes down to many factors.

• Optimal sex hormone balance
• Proper estrus cycle
• Healthy reproductive tissues
• Healthy gametes(Egg and sperm)
• Proper fetal development
• Proper timing

Circadian rhythms play an important role in the regulation of all aspects of reproduction. Evidence in mouse models as well as humans indicates that disruption of circadian rhythms impairs reproductive success.

In males, this leads to low testosterone and sperm production. In females, this alters hormonal balance during the estrus cycle, impairs reproductive tissue health, and disrupts fetal development.

The evidence clearly indicates that circadian disruption is a cause of infertility. Furthermore, the hormonal imbalance created by circadian disruption perpetuates it.

Therefore, addressing circadian rhythms is essential to reproductive success and should be one of the first steps for couples having difficulty conceiving.

In this weeks email, we’ll discuss some of the low-hanging fruit that needs to be addressed to help develop a strong circadian rhythm to improve reproductive success. If you want in, sign up using the form at the top of the page in the righthand margin.