ESPE Yearbook of Paediatric Endocrinology

s.molinari3@campus.unimib.it Eur J Endocrinol. 2021; 185: 717-728. PMID: 34519276.

Brief Summary: This retrospective study, involving two Italian centers, enrolled post-pubertal female patients who had been treated with gonadotoxic therapies for hematological malignancies and/or hematopoietic stem cell transplantation (HSCT) before the age of 18 years.

Several studies have reported the association between therapy with alkylating agents and ovarian failure but information is still lacking about the continuous relationship between increasing doses of antineoplastic drugs and reduced anti-Müllerian hormone (AMH) levels as an index of impaired ovarian reserve. The severity of gonadotoxicity depends on the cumulative burden of chemotherapy and a specific algorithm has been proposed to normalize the dose of any alkylating agent into the corresponding cyclophosphamide equivalent dose (CED), considered as a reliable tool to quantify the total exposure to gonadotoxic treatments and compare different antineoplastic protocols (1).

The aim of study was to analyze the pattern of residual ovarian function and assess the relationship between cyclophosphamide equivalent dose (CED) and anti-Müllerian hormone (AMH). Based on the analysis of the collected data, a systematic algorithm was developed to quantify iatrogenic gonadal impairment according to AMH levels. According to previous data on ovarian reserve in childhood cancer survivors AMH-SDS ≥−1.65 was considered normal, whereas values <−1.65 were classified as ‘low’. Ovarian reserve was defined as:

- normal ovarian reserve (NOR): regular menses, AMH SDS ≥ −1.65 and normal FSH levels- diminished ovarian reserve (DOR): AMH-SDS <−1.65, despite normal gonadotropins (FSH ≤ 25 UI/L) and regular menses.- premature ovarian insufficiency (POI): 4–6 months of oligo-amenorrhea associated with FSH >25 IU/L at two consecutive measurements recorded more than 4 weeks apart.

POI was diagnosed in 72.1% of women treated with HSCT and in 3.7% of non-HSCT women. DOR was present in 16.3% of women treated with HSCT and 22.2% of non-HSCT women. Conditioning regimens played a key role on ovarian outcome in HSCT patients; 100% of either total body irradiation (TBI) or busulfan-exposed patients presented ovarian impairment, while patients treated with cyclophosphamide developed POI in 44% of cases, DOR in 22%, and showed a normal ovarian reserve in the remaining cases. Similarly, AMH levels were higher amongst patients who received cyclophosphamide compared with those who received busulfan or TBI-based conditionings. Higher CED values were associated with lower AMH-SDS, with the value of 7200 g/m2 discriminating the best cut-off between DOR/POI and normal ovarian function. Age at cancer diagnosis ≥10 years negatively affected ovarian reserve.

This study confirms that radiotherapy, older age at diagnosis, and HSCT increase the likelihood of developing ovarian impairment and support the recommendation for ovarian assessment for all women treated with alkylating agents and/or radiotherapy, in particular those exposed to CED ≥ 7200 mg/m2. High gonadotropin levels and oligo-amenorrhea are still routinely used to diagnose POI, but an integrated evaluation of AMH levels, age at chemotherapy exposure, and an adequate assessment of the overall treatment-related burden could guide clinicians in providing patients with personalized counselling about fertility. The early identification of patients with ovarian reserve impairment, could lead to a prompt undertaking of fertility preservation techniques by exploiting the “opportunity window” preceding the progression into overt POI.

References: 1. Green DM, Nolan VG, Goodman PJ, Whitton JA, Srivastava D, Leisenring WM, Neglia JP, Sklar CA, Kaste SC, Hudson MMM et al. The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study. Pediatric Blood and Cancer 2014 61 53–67. (https://doi.org/10.1002/pbc.24679)