Reference standards for follicular density in ovarian cortex from birth to sexual maturity

Jasmin Hassan; Katri Knuus; Atte Lahtinen; Ilmatar Rooda; Marjut Otala; Timo Tuuri; Sebastian Gidlöf; Erik Edlund; Judith Menezes; Johan Malmros; Petra Byström; Mikael Sundin; Cecilia Langenskiöld; Hartmut Vogt; Per Frisk; Cecilia Petersen; Pauliina Damdimopoulou; Kirsi Jahnukainen

doi:10.1016/j.rbmo.2023.103287

Reference standards for follicular density in ovarian cortex from birth to sexual maturity

Reprod Biomed Online. 2023 Oct;47(4):103287. doi: 10.1016/j.rbmo.2023.103287. Epub 2023 Jul 17.

Authors

Jasmin Hassan¹, Katri Knuus², Atte Lahtinen³, Ilmatar Rooda⁴, Marjut Otala⁵, Timo Tuuri², Sebastian Gidlöf⁶, Erik Edlund⁷, Judith Menezes⁷, Johan Malmros⁸, Petra Byström⁹, Mikael Sundin⁹, Cecilia Langenskiöld¹⁰, Hartmut Vogt¹¹, Per Frisk¹², Cecilia Petersen¹³, Pauliina Damdimopoulou⁴, Kirsi Jahnukainen¹⁴

Affiliations

¹ Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden; Department of Gynaecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden. Electronic address: jasmin.hassan@ki.se.
² Department of Obstetrics and Gynaecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
³ Applied Tumour Genomics Research Programme, Faculty of Medicine, University of Helsinki, Finland; Department of Medical and Clinical Genetics, Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁴ Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden; Department of Gynaecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁵ University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁶ Department of Clinical Science, Intervention and Technology, Division of Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden; Department of Gynaecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
⁷ Department of Gynaecology and Reproductive Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁸ Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden; Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
⁹ Department of Clinical Science, Intervention and Technology, Division of Paediatrics, Karolinska Institutet, Stockholm, Sweden; Section of Paediatric Haematology, Immunology and HCT, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
¹⁰ Department of Paediatric Oncology, Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
¹¹ Crown Princess Victoria's Child and Youth Hospital, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health, Linköping University, Linköping, Sweden.
¹² Department of Women's and Children's Health, Uppsala University Children's Hospital, Uppsala, Sweden.
¹³ NORDFERTIL Research Lab Stockholm, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Department of Paediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
¹⁴ NORDFERTIL Research Lab Stockholm, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Children's Hospital, Paediatric Research Centre, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

PMID: 37603956
DOI: 10.1016/j.rbmo.2023.103287

Abstract

Research question: Are age-normalized reference values for human ovarian cortical follicular density adequate for tissue quality control in fertility preservation?

Design: Published quantitative data on the number of follicles in samples without known ovarian pathology were converted into cortical densities to create reference values. Next, a sample cohort of 126 girls (age 1-24 years, mean ± SD 11 ± 6) with cancer, severe haematological disease or Turner syndrome were used to calculate Z-scores for cortical follicular density based on the reference values.

Results: No difference was observed between Z-scores in samples from untreated patients (0.3 ± 3.5, n = 30) and patients treated with (0.5 ± 2.9, n = 48) and without (0.1 ± 1.3, n = 6) alkylating chemotherapy. Z-scores were not correlated with increasing cumulative exposure to cytostatics. Nevertheless, Z-scores in young treated patients (0-2 years -2.1 ± 3.1, n = 10, P = 0.04) were significantly lower than Z-scores in older treated patients (11-19 years, 2 ± 1.9, n = 15). Samples from patients with Turner syndrome differed significantly from samples from untreated patients (-5.2 ± 5.1, n = 24, P = 0.003), and a Z-score of -1.7 was identified as a cut-off showing good diagnostic value for identification of patients with Turner syndrome with reduced ovarian reserve. When this cut-off was applied to other patients, analysis showed that those with indications for reduced ovarian reserve (n = 15) were significantly younger (5.9 ± 4.2 versus 10.7 ± 5.9 years, P = 0.004) and, when untreated, more often had non-malignant haematologic diseases compared with those with normal ovarian reserve (n = 24, 100% versus 19%, P = 0.009).

Conclusion: Z-scores allow the estimation of genetic- and treatment-related effects on follicular density in cortical tissue from young patients stored for fertility preservation. Understanding the quality of cryopreserved tissue facilitates its use during patient counselling. More research is needed regarding the cytostatic effects found in this study.

Keywords: Child; Female fertility preservation; Follicular density; Ovarian tissue cryopreservation; Young adult; Z-score.

MeSH terms

Adolescent
Adult
Aged
Antineoplastic Agents, Alkylating
Child
Child, Preschool
Female
Humans
Infant
Ovary
Quality Control
Reference Standards
Turner Syndrome*
Young Adult

Substances

Antineoplastic Agents, Alkylating