Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement.

There are three physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime: during fetal life, in the first months after birth (mini-puberty), and at puberty.

• The first wave occurs during fetal life, the second (termed 'mini-puberty') in the first months after birth, and the third at puberty.
• After adolescence, the HPG axis remains active all through adulthood.
• In severe congenital hypogonadotropic hypogonadism (CHH), all three waves of GnRH pulsatility are absent.

Absence of fetal HPG axis activation manifests in approximately 50% of male newborns with CHH as micropenis and/or undescended testes (cryptorchidism).

• Around 50% of male newborns with severe CHH present with micropenis and/or cryptorchidism.
• These findings reflect the absence of fetal GnRH pulsatility and subsequent lack of gonadotropin-driven testosterone production.
• The lack of the mini-puberty phase further accentuates testicular immaturity in these boys.

Absent mini-puberty in males with CHH results in a low number of Sertoli cells, which has detrimental effects on later fertility.

• Sertoli cells established during mini-puberty are important for future reproductive capacity.
• The lack of the mini-puberty phase is characterized by a low number of Sertoli cells.
• The paper states that 'absent mini-puberty will have detrimental effects on later fertility in these males.'

The diagnosis of CHH is often missed in infants, and there is no consensus on optimal therapeutic management even when recognized.

• CHH is described as a rare genetic disorder characterized by a deficiency in hypothalamic GnRH secretion or action.
• The paper notes the diagnosis 'is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management.'
• The review provides a diagnostic approach to allow for early identification of these conditions.

Evidence from small case series indicates that gonadotropin replacement to mimic mini-puberty in males with CHH can produce beneficial outcomes including testis descent and normalization of testis and penile sizes.

• The evidence base consists of small case series rather than large controlled trials.
• Beneficial outcomes reported include not only testis descent but also normalization of testis and penile sizes.
• Therapeutic replacement regimens were reviewed as a current treatment option for replacement of mini-puberty in male infants with CHH.
• The paper states such regimens 'could address both reproductive and nonreproductive implications.'

Therapeutic replacement of mini-puberty with gonadotropins in males with CHH has potential implications for both reproductive and nonreproductive outcomes.

• Reproductive implications include effects on testis size, penile size, testis descent, and future fertility potential through Sertoli cell number.
• Nonreproductive implications are also identified as potential targets of therapeutic replacement, though specific nonreproductive outcomes are noted without full enumeration in the abstract.
• The review covers 'current treatment options for replacement of mini-puberty in male infants with CHH.'