Gonadal and uterine function in female survivors treated by chemotherapy, radiotherapy, and/or bone marrow transplantation for childhood malignant and non‐malignant diseases

Abstract

Objective To evaluate gonadal function and uterine volume in a cohort of female survivors treated by chemotherapy, radiotherapy, and/or stem cell transplantation (SCT) for childhood malignant and non-malignant diseases.Design An observational study.Setting S. Matteo Hospital, Pavia, Italy.Population A cohort of 135 female survivors.Methods A clinical, hormonal, and ultrasonographic evaluation. Thirty-three patients (24%) had non-malignant haematologic diseases (thalassaemia or sickle cell anaemia), 68 (50%) had leukaemia, 23 (17%) had lymphomas, and 11 (8%) had solid tumours. In total, 106 patients had received SCT, preceded by a conditioning regimen.Main outcome measures Anti-M€ ullerian hormone (AMH) and Inhibin-B, and uterine volume.Results The median concentrations of AMH and Inhibin-B in the entire cohort were 0.12 ng/ml (interquartile range, IQR, 0.1-0.5 ng/ml) and 3.5 pg/ml (IQR 0.1-13.2 pg/ml), respectively. In a stepwise ordered logistic regression analysis, conventional chemotherapy for the treatment of malignancies, as opposed to total body irradiation (TBI), was the only oncologically significant predictor of increased AMH levels (OR 4.8, 95% CI 1.9-12, P < 0.001). Conditioning treatment before or after menarche did not influence AMH concentrations (P = 0.24). The best predictor of reduced uterine volume was TBI during the preparation for the allograft (OR 3.5, 95% CI 1.4-8.4, P = 0.006). Increasing age at treatment (OR 0.86, 95% CI 0.77-0.95, P = 0.04), chemotherapy, as opposed to other treatments (OR 0.09, 95% CI 0.03-0.28, P < 0.001), and solid tumours as opposed to either leukaemia/ lymphomas or non-malignant diseases (OR 0.2, 95% CI 0.07-0.56, P = 0.002) were associated with larger uterine volumes.Conclusions Conditioning therapies for SCT, including TBI, had the worst effects on uterine volume and gonadal reserve. Increasing age at treatment and conventional chemotherapy were associated with less detrimental effects on uterine volume.

Clinical summary guide: reproduction in women with previous abdominopelvic radiotherapy or total body irradiation

“…In accordance with other studies, irradiation at a younger age was associated with smaller uterine volumes, suggesting that RT at a younger age results in more severe and irreversible uterine damage ( Beneventi et al , 2014 ). This may be due to effects on uterine development and vasculature, with the uterus unable to respond to puberty-induced growth ( Critchley et al , 2002 ).…”

“…Most of the available studies on the effect of these variables on ovarian and uterine function after treatment have included small numbers of patients, hampering subgroup analysis of radiation effects on the uterus ( Critchley et al , 2002 ; Jadoul et al , 2011 ). In one of the largest clinical follow-up studies involving a cohort of 135 female survivors (three-quarters diagnosed prior to menarche) treated with chemotherapy, RT and/or SCT for childhood malignant and non-malignant diseases, TBI had the most damaging effect on subsequent uterine volume (OR 3.5, 95% CI 1.4–8.4) ( Beneventi et al , 2014 ). However, even the use of alkylating agents in stratified analysis was also associated with a reduced uterine volume.…”

Ovarian and Uterine Functions in Female Survivors of Childhood Cancers

“…The most devastating clinical consequences are observed in survivors who were treated with TBI, exposing the uterus to radiation of >20 Gy during childhood. A significant reduction in uterine size is observed in the survivors with ovarian failure secondary to TBI (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). But uterine atrophy is not related to hypoestrogenic state induced by ovarian failure, because hormone replacement therapy does not increase uterine size, blood flow, or endometrial thickness in these survivors [32,64,65].…”

“…In addition to first-trimester abortions, mid-trimester pregnancy losses are also more frequently observed in female survivors exposed to uterine radiation than in the general population [45,64]. Wallace et al reported that pregnancy was achieved in only 4 of 38 patients who had received whole-body irradiation (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) during childhood and that all resulted in mid-trimester miscarriage [45]. Larsen et al evaluated the impact of radiation on uterine volume in 100 childhood survivors using transvaginal sonography.…”

Maximizing the clinical utility of antimüllerian hormone testing in women's health

“…Numerous cancer therapy publications have demonstrated the dramatic effects of various chemotherapeutics in reducing serum AMH levels. Some of these studies have demonstrated that AMH testing can improve treatment selection by identifying which therapies are most toxic to the ovary and which patients are most at risk for postchemotherapy ovarian insufficiency [77 ▪ ,78 ▪▪ ,79–84]. Furthermore, numerous reports are confirming that after some ovarian-related surgeries such as removal of benign cysts and endometriomas, significant reductions in AMH are observed which may persist [72 ▪ ,73 ▪▪ ,74–76] with a recent study demonstrating similar reductions with benign cysts and endometriomas and more severe reductions with bilateral procedures [85].…”