The postnatal activation of the Hypothalamic-Pituitary-Gonadal axis in males and its impact on reproductive function and health

• Applicant: Dr. Alexander S. Busch, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464240267

The Hypothalamic-Pituitary-Gonadal (HPG) axis governs reproductive function including sexual maturation in humans. The neuroendocrine axis undergoes periods of changing activity throughout life reflecting periods of growth and maturation, reproduction and senescence. During the transient postnatal activation of the axis, the so-called minipuberty, infants reach adult levels of sex-hormones before the system is silenced again after several months. The axis then remains in a state of relative quiescence for around a decade until its reactivation promotes the transition from childhood to adulthood, i.e. puberty. In boys, minipuberty - in contrast to puberty - does neither lead to the development of secondary sexual characteristics nor to the attainment of full reproductive function as silencing of its activity prevents the maturation to fully functional gonads. However, it is crucial for the physiological testicular position, virilization as well as priming of gonadal cell types for subsequent growth and maturation in puberty and adulthood. Hence, it lays the foundation for male reproductive function and fertility potential while the role of minipuberty in girls seems to be dispensable for fertility. Disordered male minipuberty, e.g. in male preterm newborns, is associated with severe short-and long-term consequences, e.g. failure of the testes to descent (undescended testes) and increased risk of infertility. Despite the lifelong impact of minipuberty on male reproductive health, the neuroendocrine regulation of its activation and silencing, its impact on early gonadal maturation as well as determinants and limits of its maturational capacity are grossly understudied. This project aims to investigate both the regulation of minipuberty in the central nervous system as well as the effect on male reproductive organs at single-cell level in an animal model, the compensatory mechanism of the system in disordered minipuberty in male preterm newborns and the overlap in the genetic etiology of undescended testes, androgen levels and birth characteristics. The project lays the foundation for the use of minipuberty as window of opportunity for early diagnosis of HPG axis related disorders and for a potential intervention in disturbed minipuberty with the aim to improve long-term reproductive function and health.

• DFG Programme: Independent Junior Research Groups