Endocrine Abstracts

Background: Hypogonadotropic hypogonadism (HH) results in deficient sex steroid production. Diagnosis, particularly in congenital HH (CHH), remains challenging, and management varies. Gonadotropin therapy is increasingly used to induce testicular maturation and spermatogenesis, though optimal regimens and accessibility remain uncertain. This study described demographics and management of HH in our centre.

Methods: Patients with HH managed at the Hong Kong Children’s Hospital from January 2019 to December 2025 were included. Patients with functional/primary hypogonadism or constitutional delay in puberty were excluded.

Results: 44 patients were included (59% males, age 16.9 ± 5.1 years); 11 (63.6% males) had CHH and 33 (57.6% males) had acquired HH. Acquired HH was most often due to brain tumour (72.2%), followed by hypoxic brain injury or brain malformation. Among those with CHH, 7 (63.6%) had anosmia/hyposmia with absent/hypoplastic olfactory bulbs on MRI. Three (1.2-3.0 years) presented with micropenis ± undescended testes, while others (15.1-27.3 years) had absent puberty. Genetic analysis revealed known HH-associated variants in 5 (CHD7, ANOS1, FGFR3). A pathogenic ZNF462 variant (Weiss-Kruszka syndrome), recently reported in a Japanese cohort, was identified in a male patient through whole-genome sequencing. Compound heterozygous variants in the POLR3A gene, causing 4H syndrome (hypomyelinating leukodystrophy, hypodontia, hypomyelination, CHH) were detected in a female. Pubertal induction began at 15.4 ± 1.9 years for males and 14.5 ± 2.3 years for females. One male completed gonadotropin therapy (rFSH for 4 months, then rFSH and hCG for 17 months). While testicular size increased from 2ml to 8ml, FSH remained <4 IU/L and semen analysis showed oligospermia. Another patient has been receiving combined rFSH and HCG therapy for 15 months with fair compliance, and testes remained at 4-6ml. Intramuscular testosterone and oral estradiol were used in the remaining cohort. DXA among ambulant patients (n = 26) showed low BMD in TBLH in 63.6% and in LS in 28.0%.

Conclusion: Genetic analysis enhanced etiologic diagnosis and identified novel CHH variants. Early experience suggests variable response to gonadotropin therapy, but long-term fertility outcomes are yet to be defined. The high prevalence of low bone mineral density underscores the need for ongoing skeletal monitoring in this population.