Prevalence of multi-nuclear and multi-ovular follicles within paediatric ovarian tissue: recommendations for...

Do premenarcheal girls have a high proportion of morphologically abnormal ovarian follicles?

A higher prevalence of follicles with an abnormal number of oocytes and nuclei was found in premenarcheal ovarian tissue compared with postmenarcheal tissue.

Morphological aberrations of ovarian follicles, including multi-nuclear oocytes and multi-ovular follicles, have been documented across species, including humans. These specific morphological aberrations, together with other types of abnormal follicles, are more prevalent in the ovaries of children and decline in number with age. However, detailed studies of the prevalence of multi-nuclear and multi-ovular follicles in paediatric ovarian tissue are limited.

This was an observational study of the ovaries of children and adolescents who underwent ovarian cryopreservation prior to chemotherapy.

The study recruited participants aged 0-18 years who underwent ovarian tissue cryopreservation at a single centre. Haematoxylin and eosin-stained slides of ovarian biopsies were scanned and analysed to determine follicle number and aberrations in morphology and the cortical area was measured. Abnormal follicles were defined as those with an abnormal number of oocytes or oocyte nuclei. Relationships with menarcheal status (premenarcheal; postmenarcheal) and age were assessed.

A total of 149 participants' ovarian samples were evaluated in the study, of whom 67 (45%) had follicles with abnormal numbers of oocytes or oocyte nuclei. Amongst 117 participants who had adequate follicle numbers, these abnormal follicle types accounted for 3.8% (902/23 891) of the total number of follicles and were significantly more common in premenarcheal girls (52/80; 65.0%) compared with postmenarcheal girls (15/37; 40.5%; P = 0.013). Ovular abnormalities (in 76.7% of abnormal follicles) were more common than nuclear abnormalities (in 23.3% of abnormal follicles; P < 0.001). Bi-ovular primordial follicles were the most common abnormality, comprising 54% of the total abnormal follicle population and were present in 41.9% of participants.

Small ovarian biopsies were analysed, which may not fully represent the whole ovary. There is also a limited number of participants in each menarcheal group.

Our study highlights that although follicle numbers are high in the prepubertal ovary, there was also a high proportion of follicles containing abnormal numbers of oocytes and oocyte nuclei. Further longitudinal and functional studies are recommended to determine whether this impacts fertility and the longevity of function following ovarian tissue grafting for restoration of fertility in these participants. Our work supports a separate multioocytic follicle class within the NICHD follicle classification, and we suggest expanding it to include a distinct multinuclear follicle category (oocyte contains more than one nucleus), as these likely represent different aberrations in oogenesis or folliculogenesis. This classification with clear definitions and nomenclature may improve consistency in reporting and facilitate future research.

This work was supported by an MRFF Grant (MRFAR000308) supporting the funding of coauthors M.J. and M.A. Y.J. is supported through a Dame Kate Campbell Fellowship, The University of Melbourne. Co-authors V.G.-L. and J.Y.M. are supported through National Institute of Health (NIH) Z1A HD009005.

No conflict of interests are declared.

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