Abstract
Purpose
Fertility impairment and recovery after haematopoietic stem cell transplantation (HSCT) have been reported in both sexes, but little is known about how they develop over time. Our aim was to describe the dynamics of fertility impairment and recovery after HSCT.
Methods
We retrieved treatment and fertility data for up to 12 years of 361 paediatric patients with malignant and non-malignant diseases from seven European centres. The patients had been treated with allogeneic HSCT between 2000 and 2005.
Results
Development of fertility impairment was observed in males (123/217, 56 %) after a median time of 2.6 years (range 0.1–11.4) and in females (82/144, 57 %) after 2.3 years (range 0.1–12.0) after HSCT. Different busulfan dosages had only a slight impact on the onset of fertility impairment (busulfan ≥16 mg/kg with a median time to fertility impairment of 2.9 vs. 3.9 years after busulfan <14 mg/kg). Recovery from fertility impairment was observed in 17 participants after a median time of 4.1 years (range 1–10.6) in females (10/144, 7 %) and 2.0 years (range 1–6.3) in males (7/217, 3 %) after fertility impairment first appeared.
Conclusions
In the light of the dynamics of fertility impairment and recovery in the HSCT patients reviewed, these patients should be counselled comprehensively regarding fertility preservation measures.
Keywords: Allogeneic haematopoietic stem cell transplantation, Fertility, Childhood, Gonadotoxic therapy, Recovery
Introduction
Due to an increasing number of haematopoietic stem cell transplantation (HSCT) survivors in recent years (European Group for Blood and Marrow Transplantation 2005), long-term side effects of this treatment are attracting increasing interest. A critical and frequent late consequence is gonadal dysfunction. In our previous study in the same cohort on the incidence of and risk factors for fertility impairment, infertility was suspected in 69 % of male and 83 % of female survivors after HSCT in childhood and adolescence (Borgmann-Staudt et al. 2012), whereas in the general population infertility occurs with a rate of 5 % (Gnoth et al. 2005). Fertility impairment affects the patient’s ability to plan a family, and having children is a quality of life issue for many childhood cancer survivors, as for other individuals (Mertens et al. 1998; Salooja et al. 2001).
Gonadal dysfunction can be induced by radiotherapy and chemotherapy (Green et al. 2009; Howell and Shalet 1998). In particular, total-body irradiation (TBI) (Anserini et al. 2002) and certain chemotherapeutics, such as alkylating agents, were shown to be highly gonadotoxic (Meistrich and Lipschultz 2001; Sherins 1993). Conditioning regimen for HSCT usually consists of TBI with 12–14 Gray (Gy) and chemotherapy with cyclophosphamide (CY, 120 mg/kg) or etoposide (VP-16, 60 mg/kg) or a combination of busulfan (BU, 16 mg/kg) and CY (120 mg/kg). BU is regarded to be highly gonadotoxic, especially in women. However, there are conflicting observations about the extent of the gonadotoxic effect of BU (Bakker et al. 2004) at different dosages.
Recovery of fertility after HSCT therapy induced gonadal dysfunction has been reported in both sexes (Mertens et al. 1998; Vatanen et al. 2014; Rovo et al. 2006). In males, the number of patients with spermatogenesis may rise with time (Rovo et al. 2006). Even though this long-term potential for recovery was also described in females (Mertens et al. 1998), damage to the ovaries is generally thought to be irreversible, leading to infertility and amenorrhoea (Howell and Shalet 2002). However, further follow-up studies to describe the dynamics of fertility impairment and possible recovery in patients after HSCT in childhood and adolescence have not been conducted. The aim of our study was to analyse the development of fertility impairment and recovery of fertility over time.
Methods
Study design and setting
This longitudinal, multicentre, retrospective study was based on a 2009 study investigating incidence of and risk factors for fertility impairment after HSCT in childhood and adolescence, with the methods having been previously described (Borgmann-Staudt et al. 2012). In contrast to the 2009 study, this longitudinal study requested yearly information about fertility parameters for a period up to 12 years after HSCT. Data were collected again from seven European paediatric centres for HSCT in Germany (Berlin, Dusseldorf, Erlangen, Frankfurt, Muenster), Austria (Vienna) and the Czech Republic (Prague). All patients were included if they were at least 12 years old at the time of the study in 2013. The fertility parameters were recorded from the patients’ long-term clinical follow-up data. They included testicular volume measurements, details on menstrual cycle, hormone replacement therapy (HRT), spermiograms, whether they had offspring and hormone analyses for follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, oestradiol, anti-mullerian hormone (AMH) and inhibin b, which were measured in routine blood tests.
Infertility criteria
Participants were classified as having impaired fertility or a suspicion of hypergonadotropic hypogonadism at FSH ≥15 IU/L, LH ≥15 IU/L, testosterone in males <2 ng/mL, oestradiol in women <30 pg/mL (Borgmann-Staudt et al. 2012). In addition to abnormal hormone levels being suspicious for hypergonadotropic hypogonadism, the following parameters were also included as criteria for ‘suspected infertility’: amenorrhoea and micro-orchidism, defined as a testicular volume <5 ml at age 14, or <8 ml at age 15, or <10 ml at age 16 or <12 ml at age 17 (Illing and Classen 2005). AMH values were evaluated as follows: values <0.1 ng/mL were regarded as indicative of a significantly diminished ovarian reserve. In these participants, infertility was suspected. Values between 0.1 and 1.0 ng/mL were regarded as indicative of a moderately diminished ovarian reserve. In these patients, infertility was deemed imminent, due to the possibility of premature ovarian failure in the next 4 years (van Rooij et al. 2004). Values of over 1.0 ng/mL were regarded as indicative of an undiminished ovarian reserve. These patients were deemed to be fertile (Jantke et al. 2012). All fertility parameters for patients taking HRT were excluded from the analysis.
Gonadotoxic therapy was defined as: pelvic irradiation >10 Gy, total-body irradiation >10 Gy in females and >4 Gy in males and the following chemotherapy doses: BU (≥0.48 g/m2), carboplatin (≥2 g/m2), cisplatin (≥0.5 g/m2), CY (≥10 g/m2), VP-16 (≥5 g/m2), ifosfamide (≥42 g/m2), melphalan (≥0.14 g/m2) and procarbazin (≥6 g/m2).
Statistical analysis
The data were analysed using the Statistical Package for Social Sciences, version 18. The dynamics of fertility impairment were analysed by gender, treatment groups, including gonadotoxic therapy and various BU dosages, using Kaplan–Meier curves and box plots. The former take censored data into account, whereas the latter do not. Therefore, median times to a fertility impairment event differ substantially between the two approaches. Our analysis of the course of fertility impairment over time included the following fertility parameters: LH/FSH ≥15 IU/l, testosterone in males <2 ng/mL, oestradiol in women <30 pg/mL, micro-orchidism and amenorrhoea. In contrast to our 2009 study, HRT only was not considered as an infertility criterion. AMH, inhibin b and spermiograms were not considered for this analysis, as there were insufficient data. Results of AMH analyses and spermiograms are therefore reported descriptively. The occurrence of one infertility indicator was considered as an infertility event. The occurrence of one fertility indicator after an infertility event was considered as recovery (in males: FSH <15 IU/l, in females: FSH <15 IU/l). The data for these participants were then checked individually for plausibility of the fertility recovery by paediatric haematologists and oncologists.
Results
Patient characteristics
A total of 361 participants were included with 60 % (n = 217) being male. Diagnoses, treatment and fertility parameter data can be seen in Table 1. The median age of the participants was 13.3 years (range 3.7–28.4) at the time of HSCT and 22.9 (range 12.5–39.2) years at the time of the study in 2013. In the total study population, 64 % female survivors (n = 92) and 71 % male survivors (n = 155) had received a gonadotoxic therapy (see methods section). Regarding BU dosages, 92 survivors had received BU dosages ≥16 mg/kg, 6 survivors ≥14–16 mg/kg and 42 survivors <14 mg/kg.
Table 1.
Characteristics of former paediatric patients from seven European centres
| Total | Female | Male | |
|---|---|---|---|
| Patients (n) | 361 | 144 (40 %) | 217 (60 %) |
| Median age at HSCT | 13.3 (3.7–28.4) years | 13.2 | 13.3 |
| Median age at study 2013 | 22.9 (12.5–39.2) years | 23.1 | 22.7 |
| Diagnoses | |||
| ALL | 113 (31 %) | 37 (25 %) | 76 (35 %) |
| AML | 41 (11 %) | 15 (10 %) | 26 (12 %) |
| SAA | 29 (8 %) | 15 (10 %) | 14 (7 %) |
| CML | 28 (8 %) | 16 (11 %) | 12 (6 %) |
| MDS | 28 (8 %) | 16 (11 %) | 12 (6 %) |
| ALD | 22 (6 %) | – | 22 (10 %) |
| FA | 12 (3 %) | 4 (3 %) | 8 (4) |
| ES | 7 (2 %) | 4 (3 %) | 3 (1 %) |
| Thalassaemia major | 2 (1 %) | – | 2 (1 %) |
| NHL | 4 (1 %) | – | 4 (2 %) |
| Other | 75 (21 %) | 37 (26 %) | 38 (18 %) |
| Gonadotoxic therapy | |||
| Yes | 247 (68 %) | 92 (64 %) | 155 (71 %) |
| No | 112 (31 %) | 62 (43 %) | 50 (23 %) |
| BU doses | |||
| 0.1 to <14 mg/kg | 42 (12 %) | 17 (12 %) | 25 (12 %) |
| 14 to <16 mg/kg | 6 (2 %) | 3 (2 %) | 3 (1 %) |
| ≥16 mg/kg | 92 (25 %) | 36 (25 %) | 56 (26 %) |
| TBI/pelvic irradiation | |||
| Yes | 156 (43 %) | 57 (40 %) | 99 (46 %) |
| No | 205 (57 %) | 87 (60 %) | 118 (54 %) |
| Hormone analysis (LH, FSH, oestradiol, testosterone, AMH) | 332 (92 %) | 135 (94 %) | 197 (91 %) |
| HRT | 95 (27 %) | 76 (53 %) | 19 (9 %) |
| Details on menstrual cycle | 55 (38 %) | – | |
| Spermiogram | – | 15 (7 %) | |
| Testicular volume | – | 124 (57 %) | |
| Offspring | 11 (3 %) | 6 (4 %) | 5 (2 %) |
ALD adrenoleukodystrophy, ALL acute lymphoblastic leukaemia, AML acute myelogenous leukaemia, CML chronic myelogenous leukaemia, ES Ewing sarcoma, FA Fanconi anaemia, MDS myelodysplastic syndrome, NHL non-Hodgkin lymphoma, SAA severe aplastic anaemia
Fertility characteristics
Results of sperm analyses were available in 15 participants. Azoospermia was detected in 14 participants after a median time of 4.5 years (range 2.4–7.5 years) after HSCT, while one patient was identified with oligozoospermia after 2.4 years to the time point of HSCT. All 15 participants had received a gonadotoxic therapy. AMH values were measured in 30 female participants. Three of them showed AMH values <0.1 ng/mL in a median time of 10.2 years (9.1–11.3 years) after HSCT and were therefore suspected as being infertile. Fifteen participants had AMH values between 0.1 and 1 mg/mL in a median time of 7.3 years after HSCT (range 4–11 years) and were therefore regarded as having a moderately diminished ovarian reserve. Further 12 participants showed AMH values >1.0 ng/ml in a median time of 6.5 years (range 4.1–9.2 years) after HSCT and were therefore deemed to be fertile.
Dynamics of fertility impairment
Based on our infertility criteria, the course of fertility impairment over time could be observed and analysed, without taking censored patients into account, in 205 (57 %) participants, of whom 123 were male and 82 female. The incidence of and time to fertility impairment were very similar in males and females. Males developed fertility impairment (123/217, 56 %) after a median time of 2.3 years (range 0.1–11.4) and females (82/144, 57 %) after a median time of 2.6 years (range 0.1–12.0). Figure 1 presents Kaplan–Meier curves of the incidence of fertility impairment by gender over time after HSCT. It could be observed that as time passed, participants were more likely to develop infertility.
Fig. 1.
Chance of staying fertile over time after HSCT. Censored: participants without signs of fertility impairment. Non-censored: n = 205
Among different treatment groups, there was a small difference in the time point to fertility impairment between males and females who received gonadotoxic therapies. Males with gonadotoxic therapy showed a fertility impairment (n = 99) after a median time of 2.4 years (range 0.1–11.4) after HSCT. In females, it was observed (n = 54) after a median time of 1.4 years (range 0.1–10.4). Female participants with less/no gonadotoxic therapy developed a fertility impairment (n = 28) after a median time of 3.8 years (range 0.1–12.0) in comparison with males (n = 24) who developed a fertility impairment after a median time of 1.8 years (range 0.2–9.0). Figure 2 shows the incidence of fertility impairment over time after HSCT. Participants who had received a gonadotoxic therapy developed fertility impairment sooner than those whose therapy was less/not gonadotoxic (Fig. 2). Patients with gonadotoxic therapy developed a fertility impairment significantly more often than patients with less/no gonadotoxic therapy (P = 0.006).
Fig. 2.
Chance of staying fertile in different treatment groups over time after HSCT. Censored: participants without signs of fertility impairment. Non-censored: n = 153
Analysing the impact of different BU dosages on the course of fertility impairment over time, only a slight difference could be observed between the various treatment groups: participants who had received a BU dosage under 14 mg/kg and with signs of fertility impairment (n = 18) developed the latter after a median time of 3.9 years (range 0.1–12.0) compared to participants with a BU dosage ≥16 mg/kg and signs of fertility impairment (n = 52) who developed a fertility impairment after a median time of 2.9 years (range 0.2–9.6). Only four participants had received BU dosages of ≥14 to <16 mg/kg and they developed fertility impairment after 2.8 years (range 0.1–6.3) (Fig. 3). In Kaplan–Meier curve analysis, participants with a BU dosage ≥16 mg/kg developed fertility impairment faster and more often in comparison with participants with a BU dosage <14 mg/kg, this especially in female patients (Fig. 3).
Fig. 3.
Time interval from HSCT to first signs of fertility impairment in different BU dosages
Recovery from fertility impairment
In 17 participants, of whom ten were female, recovery from fertility impairment was suspected. In females (10/144, 7 %), recovery of fertility occurred after a median time of 4.1 years (range 1–10.6) after first signs of fertility impairment, and 7.0 years (range 3.25–12.4) after HSCT. Eight of them had received a gonadotoxic therapy consisting of either BU/CY or TBI and CY/VP-16 conditioning therapy and four had received HRT prior to recovery of fertility. Four years after recovery of gonadal function, one female participant again showed increased FSH levels, suggesting a new ovarian insufficiency. In males (7/217, 3 %), recovery of fertility was detected after a median time of 2.0 years (range 1–6.3) after first signs of fertility impairment, and 3.4 years (range 2–10.4) after HSCT. Four participants had received a gonadotoxic therapy consisting of either BU/CY or TBI and CY/VP-16 conditioning therapy, and in one case, the survivor had been treated with HRT before fertility recovery. Eleven offspring, all healthy, were reported of by five female and three male patients that had underwent stem cell transplantation. Table 2 shows the clinical data of these patients.
Table 2.
Patients after HSCT with own offspring
| Diagnosis | Date of birth | Date of HSCT | Conditioning regimen | Details |
|---|---|---|---|---|
| Female patients (n = 5) | ||||
| ES | 1982 | 2002 |
BU 12.8 mg/kg MEL 140 mg/m2 |
One healthy baby |
| MDS | 1983 | 2001 |
THIO 15 mg/kg, FLU 160 mg/m2 |
One healthy baby, born at term 2007 |
| SAA | 1985 | 2003 | Cy 200 mg/kg | One healthy baby, born at term 2004 |
| SAA | 1986 | 2000 | Cy 200 mg/kg | Two healthy babies |
| ALCL | 1990 | 2004 |
BU 9 mg/kg Cy 9 mg/kg VP-16 800 mg/kg |
One healthy baby, born 2006 |
| Male patients (n = 3) | ||||
| ALL | 1984 | 2002 |
TBI 12 Gy VP-16 60 mg/kg |
One healthy baby, born 2011 |
| SAA | 1987 | 2003 | Cy 200 mg/kg | Three healthy babies, born at term 2005, 2006, 2007 |
| SAA | 1988 | 2004 | Cy 200 mg/kg | One healthy baby, born at term 2010 |
Discussion
Main results
Development of fertility impairment was observed in male participants after a median time of 2.3 years and in female participants after a median time of 2.6 years after HSCT. Participants with gonadotoxic therapy were more likely to develop fertility impairment more quickly in comparison with participants without gonadotoxic therapy. Higher BU dosages were observed to cause fertility impairment within a shorter time period compared to lower BU dosages. Recovery from fertility impairment was observed in 17 participants and appeared after a median time interval of 4.1 years in females and 2.0 years in males after first signs of fertility impairment.
Comparison with other studies
To our knowledge, this is the first longitudinal study evaluating fertility impairment and recovery in survivors after HSCT, taking annual fertility data into account over more than 10 years. The incidence of fertility impairment has been described previously, showing that infertility in this same cohort occurred in 69 % of male and 83 % of female patients (Borgmann-Staudt et al. 2012). In general, longitudinal studies of fertility impairment over time and recovery in survivors after HSCT are rare. A previous study on recovery of spermatogenesis after HSCT revealed that spermatozoa were found in sperm fluid analysis in 11 of 39 males (28 %). In those patients who later presented with at least some sperm production, the median time interval between transplantation and seminal fluid analysis was 12 years (Rovo et al. 2006). It has to be taken in account that the authors only looked at one time point after HSCT and so may have missed an earlier recovery of fertility impairment. Participants of our study showed signs of fertility recovery in median 3.4 years after HSCT. This difference may be explained by the fact that our study population was considerably younger at the time of HSCT (13 vs. 25 years). Being younger was observed by the authors and in our 2009 HSCT study to be associated with an increased likelihood of fertility recovery (Rovo et al. 2006; Borgmann-Staudt et al. 2012).
Previous studies found that the timing of, and potential for, recovery from gonadal dysfunction may be affected by both treatment and patient characteristics (Sanders et al. 1983). Patients undergoing HSCT for malignant diseases also often received intensive chemotherapy and/or radiotherapy prior to condition regimen. Yet explicit risk or protective factors for fertility recovery could not be defined and seem to vary between individuals. Vatanen et al. have shown that females undergoing HSCT and CY conditioning regimen only, were more likely to experience spontaneous puberty and menarche and required HRT less often (Vatanen et al. 2014).
In our study population, two out of ten females who recovered fertility were conditioned with CY only. However, the other eight had received a gonadotoxic therapy consisting of either BU/CY or TBI and CY/VP-16 conditioning regimen. This underlines the hypothesis that recovery of gonadal function seems also to be an individual phenomenon of temporary duration, as signs of fertility impairment reappeared in one participant who had recovered gonadal function. Identifying patient groups with potential for recovering fertility, in order to offer fertility counselling, remains a significant and important challenge. Given that the period of fertility recovery may be limited, patients may wish to use it as a window of opportunity to conceive naturally (Socie et al. 2003) or by assisted conception techniques (Das et al. 2012). The incidence of fertility impairment was lower in our current study in comparison with our study in 2009 on incidence of and risk factors for fertility impairment (Borgmann-Staudt et al. 2012). This difference can be explained by the fact that we did not consider HRT as an infertility criterion for this study.
BU was the major treatment-related risk factor among females in our 2009 study (Borgmann-Staudt et al. 2012). There have been few studies investigating the extent of the gonadotoxic effect of BU at different dosages (Bakker et al. 2004; Teinturier et al. 1998; Couto-Silva et al. 2001). Some studies have shown a correlation between gonadotoxicity and dosage (Bakker et al. 2004; Teinturier et al. 1998; Couto-Silva et al. 2001). In our study population, participants with a BU dosage ≥16 mg/kg showed signs of fertility impairment slightly earlier than participants with a lower BU dosage.
Limitations
The retrospective assessment of data from patient records meant the data set was not complete for all patients, especially the follow-up hormone values. For different reasons, e.g. focus on other medical problems, no clinical signs of fertility impairment or the patient’s palliative situation, hormone values were not measured every year. Values of new fertility parameters like AMH, inhibin b and ultrasound of the ovaries (antral follicle counts) were also incomplete, as these parameters were included only recently in the follow-up measurements of childhood cancer survivors. AMH values, in particular, were not measured before 2009. This fact has to be taken into account when interpreting the median time intervals for the development of fertility impairment based on AMH values. In addition, we did not include hormone values during HRT for the analysis. This may have influenced the longitudinal analysis in terms of delayed diagnosis of fertility impairment and possible recovery.
Conclusion
The results of our longitudinal study suggest that long-term survivors of HSCT develop fertility impairment shortly after the time point of treatment with a small potential to recover fertility. In the light of high incidence and dynamics of fertility impairment and recovery in HSCT patients reviewed, all patients undergoing HSCT should be counselled comprehensively regarding fertility conservation measures.
Acknowledgments
This longitudinal study was supported by the Deutsche José Carreras Leukämie-Stiftung e.V., the Berliner Krebsgesellschaft e.V., the Kind Philipp Foundation for Leukaemia Research (Kind-Philipp-Stiftung für Leukämieforschung) in association with Sponsors for the Promotion of German Science (Stifterverband für die Deutsche Wissenschaft), by the Charité University Medical Center Berlin and the University Hospital Motol Prague. We are grateful to Hashi Syedain for proof reading the manuscript.
Conflict of interest
The authors declare no conflict of interest.
Abbreviations
- AMH
Anti-mullerian hormone
- BU
Busulfan
- CY
Cyclophosphamide
- FSH
Follicle stimulating hormone
- Gy
Gray
- HRT
Hormone replacement therapy
- HSCT
Haematopoietic stem cell transplantation
- LH
Luteinizing hormone
- TBI
Total-body irradiation
- VP-16
Etoposide
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