ESPE Yearbook of Paediatric Endocrinology

FertilSteril. 2024 Oct;122(4):744-746. PMID: 38761847. doi: 10.1016/j.fertnstert.2024.05.146. [email protected]

Brief summary: This cross-sectional study investigated ovarian histology in young girls with classic galactosemia (CG) and linked these findings with hormonal and metabolic indicators of premature ovarian insufficiency.

Eight prepubertal girls with a confirmed diagnosis of CG undergoing ovarian tissue cryopreservation (OTC) via laparoscopic unilateral oophorectomy were included. Eight prepubertal girls without CG who were undergoing OTC before receiving gonadotoxic therapy for different diagnoses were included as controls. Ovarian biopsies were taken and examined for follicle count (primordial, primary, secondary), evidence of fibrous "streak" stroma or normal ovarian architecture. Hormonal and metabolic biomarkers (anti-Müllerian Hormone (AMH), FSH, LH, oestradiol and galactose-1-phosphate (gal-1-p) were measured.

Younger girls (age <5years) often had normal follicle counts, while older prepubertal girls more commonly showed absent or reduced follicles, sometimes replaced by fibrotic stroma. Most patients had low AMH, indicating early decline in ovarian reserve. Elevated FSH levels were observed while FSH bioactivity remained within normal range, supporting the hypothesis of direct ovarian damage rather than abnormal hormonal signalling. Patients with no detectable follicles also had nearly undetectable AMH and high FSH levels, supporting the association between histological damage and endocrine insufficiency. Younger age at the time of the biopsy corresponded to more intact ovarian histology and relatively preserved AMH. There was a strong negative correlation between gal-1-p values at 0–1 month and 1–6 months of life, and mean follicular density at the time of OTC.

Comment: This evidence enhances our understanding of the impact of classic galactosemia on the ovaries by linking histological findings with biochemical markers. The cross-sectional design and small sample size limit inference on the precise timeline of follicular depletion, but the findings support early fertility counselling and consideration of fertility preservation techniques (e.g., ovarian tissue cryopreservation) in childhood, where ethically and medically feasible. A longitudinal study starting in infancy with early and serial AMH monitoring and non-invasive ovarian imaging could clarify the progression rate of ovarian damage and help identify at-risk girls before significant follicular loss. Molecular analysis of ovarian cells (e.g., single-nucleus transcriptomics) may elucidate the pathophysiology of ovarian damage, such as endoplasmic reticulum (ER) stress or DNA damage pathways.