A dual origin for pituitary gonadotrophs and its relevance for reproductive function

Reproductive health is crucial for fertility, and important for overall well-being. While reproductive capacity begins at puberty, reproductive development starts much earlier, shortly after birth, during a preparatory phase called minipuberty. This period is important for future fertility in males, and brain development in both sexes. The same chemical messengers, or hormones, control minipuberty, puberty, and reproduction. These hormones, namely LH (luteinizing hormone) and FSH (follicle-stimulating hormone) are produced by the pituitary, a crucial gland located underneath the brain. LH and FSH regulate both minipuberty, puberty and reproduction itself by acting on the reproductive glands, or gonads—testes in males and ovaries in females. They stimulate the gonads to produce steroid hormones, mainly oestrogen in females and testosterone in males. Steroid hormones are essential for the production of eggs and sperm, as well as sexual development, bone strength and physical and psychological health. In the pituitary, LH and FSH are produced by specialised cells called gonadotrophs. They first appear in the embryonic pituitary, before birth. However, I have discovered that in the mouse a second population of gonadotrophs appears after birth, during minipuberty. These come from pituitary stem cells, naïve cells able to become any specialised pituitary cell, that I have previously characterised. These postnatal gonadotrophs will go on to form the majority of adult gonadotrophs. In the light of my results, studies performed in primates suggest this may also happen in this species, implying the significance of my finding in humans. This discovery is important for our understanding of the reproductive function because it shows for the first time that all gonadotrophs do not have the same origin, which suggests in turn that prenatal and postnatal gonadotrophs have unique roles or characteristics. It is also likely that these findings have an impact on diagnosis and treatment of a range of diseases affecting puberty. The way pubertal abnormalities develop is mostly unknown, and specific treatments are lacking. My project aims to characterise these two populations of gonadotrophs, in health and disease. The role of the postnatal population is likely to be important because it represents such a large proportion of adult gonadotrophs. However the smaller group of gonadotrophs already present at birth persists, and we simply do not know which role each population plays. Therefore, I aim to characterise the role of each gonadotroph population. Furthermore, I wish to examine if and how the two gonadotroph populations are affected in an animal model of absent puberty, to better understand how this disease develops, and potentially suggest adapted therapeutic approaches. Finally, I plan to identify the signals that prompt pituitary stem cells to generate gonadotrophs exclusively during minipuberty, to better understand how this period is initiated. In addition, identifying these signals could be useful to create gonadotrophs in the lab; these “gonadotrophs in a dish” would help studying diseases, drug development and regenerative medicine. In conclusion, my proposal will give new insights into reproductive function, in health and disease. Since most gonadotrophs appear shortly after birth, my findings may guide early diagnoses and treatments, before diseases manifest at puberty. Furthermore, my project will potentially help characterising the action of endocrine disrupting chemicals. These environmental polluants are known to affect reproductive function, particularly during minipuberty; the emerging population of gonadotrophs at this stage may explain this sensitivity.