The liver may play an important role in fertility, according to researchers from the University of Milan in Italy. The research was funded in part by two EU-funded projects: EWA ('Estrogens and women ageing') and DIMI ('Diagnostic molecular imaging'). EWA received almost EUR 2.4 million in funding, while DIMI clinched EUR 10.7 million in support. Both projects were funded under the 'Life sciences, genomics and biotechnology for health' Thematic area of the EU' Sixth Framework Programme (FP6). The study was recently presented in the journal Cell Metabolism.
Previous studies have suggested that diet may have an impact on fertility, but this latest research provides new insight into the important role of the liver in fertility. The study showed that oestrogen receptors in the liver are critical for maintaining fertility, and that the expression of those receptors is under the control of dietary amino acids, the building blocks of proteins.
These findings, made during experiments with mice, may have important implications for some forms of infertility and for metabolic changes that come with menopause, according to the researchers. 'This is the first time it has been demonstrated how important the liver is in fertility,' said Professor Adriana Maggi from the Pharmacology and Biotechnology unit and Director of the Centre of Excellence on Neurodegenerative Diseases at the University of Milan. 'The idea that diet may have an impact on fertility isn't totally new of course, but this explains how diet, and especially a diet poor in protein, can have a direct influence.'
Scientists had known that the liver expressed oestrogen receptors and that those receptors played some role in metabolism. But Professor Maggi said those receptors had not garnered a lot of attention, explaining that her group only became interested in them by accident. During the murine studies 'we saw that the organ that always had the highest activation of oestrogen receptor was the liver', she said. Initially they thought it was a mistake and disregarded it, but over time they began to think maybe the mice were telling them something.
The researchers discovered that the expression of those oestrogen receptors depends on dietary amino acids. Mice on a calorie-restricted diet and those lacking oestrogen receptors in their livers showed a decline in an important hormone known as IGF-1.
The scientists showed that the blood levels of the hormone dropped to levels inadequate for the correct growth of the lining of the mice's uteruses and normal progression of the oestrous cycle. However, when the calorie-restricted mice were given more protein, their reproductive cycles got back on track. Dietary fats and carbohydrates, on the other hand, had no effect on the oestrogen receptors or fertility.
The researchers suggested that this connection between amino acids, oestrogen receptor signalling in liver and reproductive functions may have clinical implications. For instance, Professor Maggi said this may explain why people who are anorexic are generally infertile, while it also suggests that diets loaded with too many carbohydrates and too little protein may hinder fertility.
Moreover, the results provide new clues for understanding the increased risk of metabolic and inflammatory disease in menopausal women. Professor Maggi said those changes may be explained in part by the lack of oestrogen action in their livers and its downstream consequences.
Today, given concerns about hormone replacement therapy, menopausal women are often treated with drugs that target one organ or another to protect against specific conditions, such as atherosclerosis or osteoporosis. Given the liver's role as a central coordinator of metabolism and producer of many other important hormones, she said drugs that 'target only the liver may solve all the problems'.