Inflammation and steroid hormones control ovulation

Diet and lifestyle 31. mar 2024 3 min PhD Fellow Malene Louise Johannsen Written by Kristian Sjøgren

Researchers have determined for the first time the levels of steroid hormones during the ovulatory process. A researcher says that this advances knowledge on fertility and how fertility treatment may have to be personalised in the future.

Ovulation is the defining point in a woman’s menstrual cycle and the first in a long series of events that can ultimately lead to the birth of a baby.

Researchers already today know much about what happens in ovulation and what can go wrong, but there are still large gaps in the overall understanding of the starting-point for one of nature’s great wonders.

Researchers in Denmark are now filling one gap by describing for the first time a woman’s entire steroid profile in connection with ovulation.

The research shows how cortisol, cortisone, progesterone and various enzymes work together to create local inflammation that releases the egg from the ovary so it can begin its long journey through the fallopian tube, attach to the uterus and potentially be fertilised.

Although the insight is new, the results are in accordance with what the researchers had expected.

“The results show exactly what we expected. Before ovulation, the level of the biologically active cortisol is low locally in the ovary but rises rapidly in the last four hours leading up to ovulation and egg extrusion. The results improve awareness of the woman’s cycle up to ovulation and may be used to optimise future fertility treatment,” explains a researcher behind the study, Malene Louise Johannsen, PhD Fellow, Laboratory of Reproductive Biology, Rigshospitalet, Copenhagen, Denmark.

The research has been published in Human Reproduction.

Local inflammation triggers ovulation

Cortisol, cortisone, progesterone and other steroid hormones have crucial roles in ovulation and fertility in general.

Ovulation is a controlled local inflammatory process that is initiated by an increase in the concentration of gonadotropins, which then stimulates inflammatory signalling cascades that break down the membrane of the follicle wall and release the egg into the fallopian tube.

Once the egg has been released, inflammation must be stopped to limit damage to the ovary – a process controlled by cortisol.

Then the level of progesterone needs to be elevated, because this helps to ensure that the egg can attach itself to the uterus and that cortisol is active.

“The focus in infertility has long been on progesterone, but many women still cannot conceive even if they have sufficient progesterone. This suggests that the interaction between progesterone, cortisol, cortisone and other hormones may not be in balance – hence this study,” says Malene Louise Johannsen.

Measuring steroid hormones at different times

The researchers examined follicular fluid from 50 women undergoing fertility treatment at Zealand University Hospital in Holbæk and Køge.

The women’s follicles were stimulated during the fertility treatment, and the researchers then examined the levels of 16 steroid hormones just before the fertility treatment and 12, 17, 32 and 36 hours after inducing ovulation.

The researchers also measured the levels of the enzymes that help to raise or lower the levels of cortisol and cortisone. HSD11B type 1 turns cortisone into cortisol, and HSD11B type 2 converts cortisol back into cortisone, which is not biologically active.

Results as expected

The results were as the researchers had expected.

In the first 17 hours after induction of ovulation, cortisol levels are low, only a few nanomolar, because the egg is not yet ready to be released. In contrast, the levels of cortisone are high and the activity of HSD11B type 1 is very low.

Malene Louise Johannsen explains that between 32 and 36 hours typically elapse before fertility treatment results in ovulation.

The researchers observed this in the steroid profile, with levels of cortisol rising very strongly right up to ovulation and peaking at 100–140 nanomolar. So do the levels of HSD11B type 1, which is activated to increase the levels of cortisol to create the required anti-inflammatory effect of cortisol to curb the inflammation in the ovary once the egg has been released.

HSD11B type 1 levels increased 20,000 times

In contrast, the researchers found that the levels of cortisone and HSD11B type 2 are high in the first 17 hours after fertility treatment starts but drop abruptly towards ovulation.

The researchers also found that the levels of progesterone rise before ovulation as a sign that the uterus is getting ready to receive the egg.

“Everything is as we had imagined, but now we also have numbers. This makes us more aware of the temporal activity of steroid hormones in connection with ovulation. The next step will be for us to investigate the process for women not receiving fertility treatment. What does it look like when we do not induce ovulation, and do women undergoing fertility treatment differ from women who are not?” explains Malene Louise Johannsen.

More personalised fertility treatment

Malene Louise Johannsen thinks that fertility treatment can be increasingly optimised by improving understanding of the processes involved in all stages of a pregnancy.

This applies both generally to women struggling to become pregnant but also at an individual level.

“We still do not understand many aspects of this, and we therefore offer all women the same type of fertility treatment. We would like to investigate how we can optimise fertility treatment for each individual woman’s needs. However, this requires much better understanding of what happens in connection with ovulation and how women vary,” concludes Malene Louise Johannsen.

The intrafollicular concentrations of biologically active cortisol in women rise abruptly shortly before ovulation and follicular rupture” has been published in Human Reproduction. The research was supported by Rigshospitalet, Interreg Öresund–Kattegat–Skagerrak through ReproUnion – Platform for Driving Reproductive Health Innovation, the Region Zealand Research Fund and the Novo Nordisk Foundation.

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