The challenge of defining predictive parameters for fertility preservation counseling in young females with Turner syndrome

Abstract

Sir, Recently, a review by Nawroth et al and an accompanying editorial on fertility preservation (FP) counseling in females with Turner syndrome (TS) by Rodriguez-Wallberg and Landin-Wilhelmsen were published.1, 2 We agree with the authors of both articles that FP counseling in TS patients is challenging because the decision to perform FP depends on multiple factors and not just on the ovarian reserve. Nawroth et al present in their review a flowchart to summarize their recommendations, which in our opinion is far too simplistic. This has been partially covered in the editorial.2 However, we would like to address several additional points that require further attention. First, the flowchart indicates that cardiologic screening should only be provided to monosomic TS patients. We agree with the opinion expressed in the editorial that cardiologic screening should be provided to all TS patients, in accordance with the Swedish guidelines for management of women and girls with TS.2 In line with the Cincinnati clinical practice guideline of TS patients, each girl in the Netherlands diagnosed with TS will have a diagnostic work-up phase, including cardiologic screening, which is similar to the Health Care Program in Sweden. Although it is reported that mosaic TS patients have a lower risk of cardiovascular and obstetric complications compared with other TS patients, cardiovascular complications can occur in all women with TS.3 Therefore, the karyotype of TS patients cannot be used as a predictive marker for cardiovascular risk evaluation. Secondly, the flowchart of Nawroth et al divides TS in two groups based on karyotypical aberrations. Peek et al have recently shown that the level of mosaicism in extra-ovarian cells was not predictive of the level of mosaicism in ovarian cells in the same patient.4 These findings have been substantiated by a case report of a girl who was initially diagnosed with 45,X, whereas a cryptic mosaicism was present in the ovary.5 Therefore, it is difficult to assign TS patients to a particular group, as cryptic cell lines may be present in the ovary that are likely to determine its reproductive potential. In our opinion, an international standard should be developed, describing which peripheral cells and number of cells should be karyotyped in order to assign a TS patient to a specific group. Thirdly, Nawroth et al gave anti-Müllerian hormone (AMH) a central position in their flowchart despite their statement that the prognostic value of AMH in determining the ovarian reserve in young TS patients is limited. Hagen et al reported that AMH levels correlated significantly with ovarian function in a relatively small group of TS patients aged 12-25 years and stated that this marker might be used for this group during FP counseling.6 However, the flowchart also presents AMH as a prognostic marker for prepubertal children, whereas it remains unclear what the prognostic value of AMH is in this group. Furthermore, AMH levels measured at different time points can vary considerably in the same patient, due to biological variability and inter-test variability of AMH assays. Therefore, adequate interpretation of AMH levels in this group is difficult. FP counseling in young TS patients is challenging and reliable predictive parameters are required to optimize this process. AMH should be interpreted with caution, due to its known limitations.