Treatment of gonadotropin deficiency during the first year of life: long-term observation and outcome in five boys.

<bold>Study Question: </bold>What is the peripubertal outcome of recombinant human FSH (r-hFSH) treatment during minipuberty in boys with congenital hypogonadotropic hypogonadism (CHH)?<bold>Summary Answer: </bold>Sertoli-cell response to r-hFSH, given during the minipuberty of infancy, appears insufficient to maintain Sertoli cell function throughout childhood, as evaluated by inhibin B measurements.<bold>What Is Known Already: </bold>Severe CHH in boys can be diagnosed during the minipuberty of infancy. Combined gonadotropin treatment at that age is suggested to improve testicular endocrine function and future fertility, yet long-term evidence is lacking.<bold>Study Design, Size, Duration: </bold>In this retrospective cohort study, we describe five CHH boys treated with r-hFSH in Helsinki University Hospital or Kuopio University Hospital between 2004 and 2018. Immediate follow-up data (0.1-1.4 months after cessation of the gonadotropin therapy) was available for four boys and long-term observations (at the age of 10.0-12.8 years) was available for three boys. As a retrospective control cohort, we provide inhibin B values of eight untreated CHH boys at the age of 12.7-17.8 years.<bold>Participants/materials, Setting, Methods: </bold>Four patients had combined pituitary hormone deficiency, and one had CHARGE syndrome due to a CHD7 mutation. The patients were treated at the age of 0.7-4.2 months with r-hFSH (3.4 IU/kg-7.5 IU/kg per week in 2 or 3 s.c. doses for 3-4.5 months) combined with T (25 mg i.m. monthly for three months for the treatment of micropenis). Inhibin B was chosen as the primary outcome measure.<bold>Main Results and the Role Of Chance: </bold>During the r-hFSH + T treatment, inhibin B increased from 76 ± 18 ng/l to 176 ± 80 ng/l (P = 0.04) and penile length increased by 81 ± 50% (P = 0.04). Unexpectedly, two boys with robust inhibin B responses in infancy demonstrated low inhibin B values in peripuberty: declining from 290 ng/l (4 months) to 16 ng/l (12.4 years), and from 207 ng/l (6 months) to 21 ng/l (12.8 years). All boys underwent orchiopexy at 2.0 ± 0.7 years of age. Inhibin B values in long-term follow-up, available for the three boys, did not significantly differ from the untreated CHH controls.<bold>Limitations, Reasons For Caution: </bold>Limitations of this retrospective study are the small number and heterogeneity of the patients and their treatment schemes.<bold>Wider Implications Of the Findings: </bold>We describe the first long-term follow-up data on CHH boys treated with r-hFSH and T as infants. The results from this small patient series suggest that the effects of infant r-hFSH treatment may be transient, and further longitudinal studies are required to determine the efficacy of this treatment approach to optimise the fertility potential in this patient population.<bold>Study Funding/competing Interest(s): </bold>This work was supported by the Finnish foundation for Pediatric Research, the Academy of Finland and the Emil Aaltonen Foundation. The authors have no competing interests.<bold>Trial Registration Number: </bold>Non-applicable. [ABSTRACT FROM AUTHOR]