Mar 17, 2026
3 min read
In this quest to find the cause of population fertility problems, the focus is always on the ovaries and testicles, but a research…
In an effort to find the causes of people's fertility problems, the focus is always on the ovaries and testicles, but research that had a different initial aim ultimately found that the 'switch' of fertility was not in the genitals, but in the brain's immune cells.The study was published today in Science and was directed by Eva González-Suárez, director of the Transformation and Metastasis Group at the National Cancer Research Center (CNIO).
Science has long known that our brains, particularly neurons, control everything, including reproduction.The discovery of this work brings two more elements into the equation: microglia (brain defense cells) and the RANK protein.others send signs of maturation to the gonads (ovaries or testes).
Research has shown that the effects of these GnRH hormones are caused by immune cells, known as microglia.They are the type of macrophages that are best known for their work as a 'cleaning service', phagocytosing waste ('eating' cellular waste, bacteria, etc.) from the nerves.This function is improved or worsened depending on the protein RANK, to the point that microglia without RANK get their phagocytosis down, that is, they 'eat' more." If the microglia do not do this phagocytosis function, the reneurons are the same, they no longer work and the animals fail to reproduce," explains González-Suárez.
If this researcher knows anything, it's about that protein RANK: his group discovered its important role in the development of breast cancer in 2010. RANK is also involved in bone regeneration and mammary gland development."My PhD thesis began with the question of whether the RANK protein has a role in the development of breast tissue during adulthood", postdoctoral researcher in the González-Suárez laboratory and first author of the paper Alejandro Collado explains.The researcher credits Collado's creativity to thinking differently and stepping out of his comfort zone, which led to new discoveries that had nothing to do with his workplace.
To do this, it is necessary to turn to experts in other fields, such as childbirth.When they saw that there was a lack of RANK in breast development during puberty, and this was not due to a specific defect in the mother's cells, but because of "a significant decrease in the level of the sex hormone estrogen. It was here that we thought that this decrease in the level of estrogen and sex hormones could have the same effect on men, and the level of testosterone also begins to decrease.
Rather than ignore this effect because it was not their specialty, they turned to Manuel Dena-Simpierre of the University of Córdoba and a world expert on fertility."We met him at a conference and he was fundamental because he opened doors to many collaborators, including the Swiss group [Nelly Pitteleoud, of the Center Hospitalier Universitaire Vaudois (CHUV)], Vincent Prevot's group, experts in GnRH neurons in France [French National Institute of Health] [Raphael Fernandez Chacon, Institute of Biomedicine], who did not work in fertility, but in other contexts.As experts in microglia, we arrived at our discovery thanks to everyone's contributions.
After seeing low levels of estrogen and testosterone, they learned that changes in the ovaries and testes, whose development is controlled by pituitary hormones (LH and FSH) that are regulated by GnRH neurons, took another step, and that was to see if there were any changes by removing RANK from these neurons."We looked at it, and we saw the same effect in the mouse model that we started by knocking out those immune cells. That's when animals with the low sex hormone don't develop to puberty. We only saw that when we removed RANK, or just the microcells in the body."
They noticed that the mice were still in the baby stage, not developing sexually.But they did the same in adult mice that had reached sexual maturity, and by removing RANK - again throughout the body and only in microglia - there was a reduction." Fertility was interrupted: the size of the testes decreased by about 20-30% and the animals became infertile."
This sheds light on a rare disease
The study also shed light on a rare disease, congenital hypogonadotropic hypogonadism."Our animals that failed to reach sexual maturity due to this RANK deficiency had the same characteristics as patients with this disease, which is precisely characterized by not reaching sexual maturity—hypogonadism which means thin gonads. That's when they worked together."with the Swiss group, which is an expert on this disease, in which different genes are involved."In some patients it is known which genetic mutation they have for the development of hypogonadism, but in half of the patients it is not known. We analyzed our RANK to see if the patients might have changes in this gene, and we found that changes in RANK explain the disease in some patients who did not know why they developed it before."
González-Suárez clearly explains that there are two types of patients: those who have a change in embryonic development, which causes disability and death of the head (called Kallmann syndrome) and those who change after birth, keeping their head."We found a change in RANK in all types of patients. That's why we made a sample of mice to remove the protein. It made us do this because it seems that the defect is not embryonic development, we understand that it can continue and can affect reproduction in adults."
Another interesting aspect, he emphasizes, "is age-related rank changes at menarche (first menstruation) and menopause. We didn't find that there was already evidence in the scientific literature, but so far it was the only correlation with rank and fertility, and it was very clear in patients with hypogonadism."
Implications for other studies
González-Suárez reflects: "Like all great discoveries, it raises more questions than it answers. "When you get new research, the more questions it raises, the more important it is."
On the one hand, he "investigates the effect on fertility, which is a very sensitive axis. The person has to be completely healthy and many things change that".The researchers emphasize that this is beginning to be understood in an integrated model of the "non-accelerated" organism.The effects on fertility are not necessarily related to the ovaries or testes, nor are they necessarily at the level of the brain, and may not be neurons, as in this study, or even immune cells may be the main players.
But it also began to appear that microglia (cleaning services) are more important than previously thought in the control of various processes.there are emotions, and there are also other possible axes: hunger (which opens the door to the fact that there is a big part in the pain) or stress, because now all hypotheses need to be investigated.
His group, dedicated to breast cancer, will investigate in depth the role of microglia in brain metastases because, according to the researcher, there is more and more evidence of this new discipline called cancer neuroscience where, for a long time, the relationship of cancer with tumor cells, what happened, was discussed again - and it continues - now reveals the importance of this central system.Tumors and Tumors Alter the Nervous System This has now opened up a two-part discipline that has always done little, which is neuroscientists, neuroscience people, and cancer researchers.
