Hormone Therapy During Infancy or Early Childhood for Patients with Hypogonadotropic Hypogonadism, Klinefelter or Turner Syndrome: Has the Time Come?

Minipuberty is a physiological window of sex hormone activity in early life that may have lasting effects on reproductive, cognitive, and behavioral development.

• Minipuberty occurs in the first months of life and involves activation of the hypothalamic-pituitary-gonadal axis.
• In boys, testosterone and inhibin B rise during minipuberty, associated with Leydig and Sertoli cell activity and germ cell maturation.
• In girls, FSH and estradiol levels are elevated during the first months of life.
• Disruption of minipuberty, as seen in hypogonadotropic hypogonadism (HH), Klinefelter syndrome (KS), and Turner syndrome (TS), may have consequences for future fertility and neurodevelopment.

Hormone replacement during infancy in boys with hypogonadotropic hypogonadism using gonadotropins can mimic minipuberty and improve testicular and penile outcomes.

• Treatment with FSH and LH (or hCG) during minipuberty in boys with congenital HH has been shown to increase testicular volume and penile length.
• Gonadotropin treatment has been associated with increases in inhibin B and testosterone levels, suggesting Sertoli and Leydig cell stimulation.
• Some studies reported increased germ cell counts following early gonadotropin treatment, suggesting potential benefits for future fertility.
• Sample sizes in published studies have been small, limiting the ability to draw definitive conclusions about long-term outcomes.

Early testosterone treatment in boys with Klinefelter syndrome during minipuberty has shown potential benefits for neurodevelopmental and physical outcomes.

• Boys with KS have reduced testosterone levels and altered minipuberty, with lower testosterone and higher gonadotropin levels compared to controls.
• Early testosterone supplementation in infant boys with KS has been explored in small pilot studies showing potential improvements in motor and language development.
• Testicular histology in KS shows progressive loss of germ cells beginning in infancy, suggesting a rationale for early intervention.
• Long-term data on fertility outcomes and safety of early testosterone treatment in KS are lacking.

Girls with Turner syndrome have ovarian insufficiency from early life, and early estrogen treatment during infancy has been proposed but evidence remains limited.

• Girls with TS have elevated FSH and low estradiol levels in infancy, reflecting primary ovarian insufficiency.
• Early estrogen replacement has been proposed to mimic the normal minipuberty window and potentially benefit neurodevelopment and uterine development.
• Published data on early estrogen treatment in TS infants are scarce, with very few prospective studies available.
• Concerns about potential adverse effects of early sex steroid exposure, including effects on growth, require further investigation.

Current evidence for routine early hormone treatment in HH, KS, or TS is insufficient, and large prospective studies with long-term follow-up are needed.

• Existing studies are characterized by small sample sizes, heterogeneous treatment protocols, and short follow-up durations.
• Outcomes including fertility, neurodevelopment, behavior, and quality of life require assessment in large cohorts.
• The authors state there is 'a need to pursue research in this area, with large prospective cohorts and long-term data before these treatments can be routinely considered.'
• Ethical considerations regarding treatment of asymptomatic infants and the need for standardized protocols are highlighted.