Endocrine Abstracts

Context: Premature ovarian insufficiency (POI) affects approximately 1-3% of women. Clinical presentations are heterogeneous and the underlying etiologies remain unknown in the majority of cases.

Objective/aim: To characterize presentations of POI and to evaluate the distribution of underlying etiologies in women with newly diagnosed POI of unknown cause.

Design: Prospective study of 100 women with newly diagnosed POI. Autoimmunity was examined by radio immune assays of autoantibodies associated with POI, i.e. 21-hydroxylase (21 OH), cholesterol side-chain cleavage enzyme (SCC), 17α-hydroxylase (17 OH), and NALP5. Extensive chromosomal and genetic analyses were performed in all, including FMR-1 premutation sequencing and next generation sequencing (NGS) of 100 POI associated genes.

Results: Three percent had autoimmune POI based on the presence of 21OH and SCC autoantibodies. Copy number profiling or chromosome analysis revealed X-chromosome abnormalities in 5%, and a large deletion on chromosome 8 in one patient. FMR-1 premutations were identified in 3%. NGS analysis found genetic variants classified as likely causes of POI in approximately one third of cases. These included genes SOHLH2, STAG3 and EIF4ENIF1. Furthermore, several patients carried highly suspicious variants of unknown significance (VUS) in genes such as SOX8, BUB1B and C14ORF39. One patient with primary amenorrhea was homozygous for a rare missense variant in MCM8. A family history of POI was less common (10% vs 28% vs P 0.040) and fewer women reported previous pregnancies (38% vs 61%, P 0.041), in genetic compared to idiopathic POI. FSH levels were higher in genetic compared with idiopathic POI (53.4 (4.0-149.2] vs 37.3 [1.6-120] IU/l, P 0.043]. There were no significant differences between the groups in frequency of primary amenorrhea (15%), timing of menarche (13 [9-17] years) or age at secondary amenorrhea (33 [12-3] years). A larger proportion of women with African heritage carried a VUS (9/17).

Conclusion: In women with newly diagnosed POI, screening for chromosomal abnormalities and FMR mutations identified genetic etiology in 8%, whereas the extensive NGS panel revealed a possible underlying genetic etiology in more than one third, actualizing the discussion of which tests should be a part of diagnostic screening in clinical practice.