Fertility After Allogeneic Haematopoietic Stem Cell Transplantation in Childhood and Adolescence

ORIGINAL ARTICLE Fertility after allogeneic haematopoietic stem cell transplantation in childhood and adolescence

A Borgmann-Staudt1, R Rendtorff1, S Reinmuth1, C Hohmann2, T Keil2, FR Schuster3, W Holter4, K Ehlert5, P Keslova6, A Lawitschka7, A Jarisch8 and G Strauss1

1Department of Paediatric Oncology and Haematology, Charite´-Universita¨tsmedizin, Berlin, Germany; 2Institute of Social Medicine, Epidemiology and Health Economics, Charite´-Universita¨tsmedizin, Berlin, Germany; 3Clinic of Pediatric Oncology, Hematology and Clinical Immunology, University Dusseldorf, Medical Faculty, Center for Child and Adolescent Health, Dusseldorf, Germany; 4Department of Immunology and Oncology, Department of Paediatrics, Erlangen University Hospital, Erlangen, Germany; 5Department of Paediatric Haematology and Oncology, University Children’s Hospital Muenster, Muenster, Germany; 6Department of Paediatric Haematology and Oncology, Motol University Hospital, Prague, Czech Republic; 7St Anna Children’s Hospital and Children’s Cancer Research Institute (CCRI), Vienna, Austria and 8Department of Haematology, Oncology, University of Frankfurt Hospital, Frankfurt am Main, Germany

Infertility is a major late effect in patients receiving Keywords: allogeneic haematopoietic stem cell trans- haematopoietic stem cell transplantation (HSCT). The plantation; cytotoxic therapy; pregnancy outcome; fertility; aim of this study was to determine the proportion of childhood patients having fertility impairment after allogeneic HSCT in childhood/adolescence and to identify the potential risk factors. Treatment and fertility data of paediatric patients with malignant and non-malignant diseases treated with allogeneic HSCT between 2000 and 2005 Introduction were collected from seven European centres. Data were obtained for 138 female and 206 male patients after a The numbers of long-term survivors following haemato- median follow-up of 6 years (range 3–12). The patients’ poietic stem cell transplantation (HSCT) have been 1 median age was 13 years (range 4–28) at the time of noticeably increasing in recent years. Preparative regimens HSCT and 19 (range 12–35) years at the time of the are associated with a high risk of infertility, and young enquiry. Seven children were born to the overall group, all patients wish to have an unrestricted quality of life as at term and healthy. Fertility impairment was suspected in adults, including, in most cases, having children of their 69% males and 83% females. Start of treatment at age own.2,3 X13 years was a risk factor in females (odds ratio (OR) Studies have shown that the infertility induced by 4.7; 95% confidence interval (CI), 1.5 to 14.9), whereas cytostatic drugs is dependent on type and dosage of the pre-pubertal therapy was a risk factor in males (OR 0.4; drug used, and also on the patients’ age at the time of 4–7 95% CI, 0.2 to 0.8). The major treatment-related risk treatment. The most common conditioning regimen used factors were BU in females (OR 47.4; 95% CI, 5.4 to are 12–14 Gy of TBI and CY (120 mg/kg) or etoposide (VP- 418.1) and TBI in males (OR 7.7; 95% CI, 2.3 to 25.4). 16, 60 mg/kg) or a combination of BU (16 mg/kg) and CY In light of the significant proportion of HSCT patients (120 mg/kg). A number of small studies conducted with reviewed with impaired fertility, fertility conserva- adults have shown that VP-16, BU and CY, along with tion procedures should be considered for all patients other cytostatic drugs, can lead to fertility impairment, undergoing HSCT, particularly those receiving TBI or depending on the dose administered.8,9 BU-based preparative regimens. Radiotherapy-induced gonadal damage is dose- and age- Bone Marrow Transplantation (2012) 47, 271–276; dependent in both sexes. In men, doses above 4 Gy can lead doi:10.1038/bmt.2011.78; published online 11 April 2011 to irreversible azoospermia.2,10 Because of the lower sensitivity of testosterone-producing Leydig cells, reduced testosterone values are only expected after a radiation dose of 20 Gy.11 Potential for recovery with increasing periods of time since HSCT has been reported,2 but if damage to the Correspondence: Dr A Borgmann-Staudt, Charite´-Universita¨tsmedizin ovaries has occurred once, it is usually thought to be Berlin, Campus Virchow-Klinikum, Klinik fu¨rPa¨diatrie m. S. Onkolo- irreversible and can lead to infertility and amenorrhoea.12 gie/Ha¨matologie, Augustenburger Platz 1, Mittelallee 6a, 13353 Berlin, Even in pre-menarcheal girls, an ovarian dosage of 15 Gy Germany. 13 E-mail: [email protected] can lead to irreversible fertility impairment. Impaired Received 13 September 2010; revised 15 February 2011; accepted 21 fertility in females seems to be closely related to the February 2011; published online 11 April 2011 destruction of oocytes, which also impairs sex steroid Fertility after HSCT in childhood and adolescence A Borgmann et al 272 production. Ovarian biopsies performed in patients under- common in males compared with females. A conditioning going chemoradiotherapy showed ovarian damage accom- regimen without TBI was more common in females than panied by fibrosis, with no evidence of follicular males: 61 versus 54% (Table 1). maturation.14–17 At a median of 6 years (range 3–12 years) after HSCT 22 Pregnancies do occur among patients who have under- of the 133 females (17%) and 59 of the 190 males with gone HSCT as children; however, they are rare. The aims of data on fertility (31%) seemed to be fertile. Analysing this study were to identify pregnancies and their outcomes fertility separately for malignant and non-malignant as well as to determine fertility status and possible risk diagnoses, we found that 21% of the patients with factors for infertility in former patients treated at seven malignant and 42% of the patients with non-malignant European HSCT centres. diagnoses were presumed fertile. Five participants (three female and two male) were reported to have had babies, all born at term and healthy. None had received TBI. Patients and methods One female experienced amenorrhoea after the birth of her child (Table 2). In this retrospective study, data were collected from seven paediatric centres for HSCT in Germany (Berlin, Du¨ssel- Females dorf, Erlangen, Frankfurt, Muenster), Austria (Vienna) Based on our criteria, 111 (83%) of the 133 females with and the Czech Republic (Prague). Information was data on fertility were classified as being infertile: 9 out of 38 requested regarding fertility parameters and the course of women with information on their menstrual cycle had pregnancies in former paediatric patients who had received amenorrhoea, 68 were receiving hormone substitution and allogeneic HSCT in the period 2000–2005. All patients 42 of the women not taking hormone replacement therapy were included if they were at least 12 years old at the time had abnormal values on hormone analysis (FSH415 IU/L, of the study in 2009. The fertility parameters used were n ¼ 26; LH415 IU/l, n ¼ 21; oestradiol 30 pg/mL, taken from the patients’ long-term follow-up data, such as o n ¼ 31). In 10 of the 111 patients classified as infertile, spermiograms, testicular volume measurements, details of hormone substitution was the only criterion for suspected menstrual cycles and hormone substitution, as well as infertility. It is possible that some of these 10 women only hormone analyses for luteinizing hormone (LH), follicle- used hormone substitution for contraceptive reasons mean- stimulating hormone (FSH), testosterone and oestrogen. ing that the infertility rate may be lower than 83%. Patients were classified as having impaired fertility or a Females aged 1–12 years at the time of HSCT had lower suspicion of hypergonadotropic hypogonadism at FSH medians of LH and FSH, which were both within the 415 IU/L, LH415 IU/L, testosterone in males 2 ng/mL o normal range ( 15 IU/L), compared with those aged 13 or and oestradiol in women 30 pg/mL. In addition to o o older at the time of HSCT (Table 3). Comparing the two abnormal hormone levels suspicious for hypergonadotropic age groups, suspected infertility was present in 38 of 53 hypogonadism, the following parameters were also in- (72%) participants treated at ages 1–12, compared with 73 cluded as criteria for ‘suspected infertility’: amenorrhoea, (91%) of 80 who were treated at age 13 or later (P ¼ 0.003). azoospermia, hormone replacement therapy and microorchidism, defined as a testicular volume of o12 mL.18 For our analysis, based on patient records, we defined puberty Fifty-four females received TBI with a median of 12.0 Gy status in two categories: ‘Pre-puberty’ for children aged up (range 2.0–14.4 Gy) to 12 years and ‘puberty’ for children aged 13 years and Slightly more of the females who underwent TBI had signs older at the time of HSCT. of suspected infertility (46 of 52, 89%) compared with those The data were analysed using the Statistical Package for without TBI (65 of 81, 80%), but this difference was not the Social Sciences, version 17 (IBM Corporation, Somers, statistically significant. NY, USA). Mann–Whitney U tests (for continuous Four females received TLI, elevated gonadotropin levels variables) and w2 tests (for categorical variables) were were seen in one patient. Table 4 gives an overview of seven conducted to test differences between groups (significance female patients who had received non-myeloablative level Po0.05). Adjusted odds ratios (ORs) and 95% therapy. confidence intervals (CIs) were calculated using multi- In the group of females, BU (administered at a median variable logistic regression analyses to estimate the impact dosage of 15 mg/kg; range 2.0–17.8) compared with females of different chemotherapeutic agents and types of radio- who did not receive BU, represented a significant risk therapy on fertility status. factor for infertility in comparison with the other chemotherapeutic agents. In the group of female participants treated with BU, both median LH and median FSH values Results were significantly higher than in those not receiving BU treatment (Table 3). There were also significantly more Out of 344 patients included, 60% were male. The female participants with suspected infertility after BU distribution of diagnoses showed some gender-specific therapy (50 of 51, 98%) than not after BU therapy (61 of differences: acute lymphoblastic leukaemia and adrenoleu- 82, 74%, Po0.001). kodystrophy were relatively more common, whereas In multivariable logistic regression analyses, puberty chronic lymphoblastic leukaemia, myelodysplastic syn- compared with pre-puberty (OR 4.7; 95% CI, 1.5 to 14.9), drome and severe aplastic anaemia were relatively less TBI versus no TBI (OR 4.9; 95% CI, 1.2 to 19.9;)

Bone Marrow Transplantation Fertility after HSCT in childhood and adolescence A Borgmann et al 273 Table 1 Characteristics of the former paediatric patients from seven European centres

Total, n ¼ 344 Female, n ¼ 138 Male, n ¼ 206

Median age (range) at HSCT 13 (4–28) years 13 (4–27) years 13 (4–28) years Median age (range) at enquiry 19 (12–35) years 19 (12–34) years 19 (12–35) years

Diagnoses ALL 114 (33%) 35 (25%) 79 (38%) AML 42 (12%) 15 (11%) 27 (13%) CML 31 (9%) 19 (14%) 12 (6%) MDS 30 (9%) 16 (12%) 14 (7%) SAA 29 (8%) 15 (11%) 14 (7%) ALD 23 (7%) – 23 (11%) FA 12 (4%) 4 (3%) 8 (4%) ES 10 (3%) 4 (3%) 6 (3%) Thalassaemia major 7 (2%) 4 (3%) 3 (2%) NHL 5 (2%) 1 (1%) 4 (2%) Other (ALCL, AUL, BAL, CLL, CVID, Evans syndrome, 41 (12%) 25 (18%) 16 (8%) fatal mononucleosis, Hodgkin’s disease, JMML)

Conditioning regimens Without TBI 196 (57%) 84 (61%) 112 (54%) BU/CY 64 (33%) 25 39 BU/CY/MEL 36 (18%) 15 21 CY 22 (11%) 11 11 Others 74 (38%) 33 41

Conditioning regimens With TBIa 148 (43%) 54 (39%) 94 (46%) TBI/VP-16 95 (64%) 31 64 TBI/CY 28 (19%) 14 14 TBI/others 25 (17%) 9 16

Hormone analysis (LH, FSH, oestradiol, testosteron) 323 (94%) 133 190 Hormonal substitution 78 (23%) 68 10 Details on menstrual cycle 38 — Spermiogram —8 Testicular volume —99

Abbreviations: ALCL ¼ anaplastic large cell lymphoma; ALD ¼ adrenoleukodystrophy; AUL ¼ acute undifferentiated leukaemia; BAL ¼ acute biphenotypic leukaemia; CVID ¼ common variable immunodeﬁencency; ES ¼ Ewing sarcoma; FA ¼ Fanconi anaemia; FSH ¼ follicle-stimulating hormone; HSCT ¼ haematopoeitic stem cell transplantation; JMML ¼ juvenile myelomonocytic leukaemia, LH ¼ luteinizing hormone; MDS ¼ myelodysplastic syndrome; MEL ¼ melphalan; NHL ¼ non-Hodgkin’s lymphoma; SAA ¼ severe aplastic anaemia; VP-16 ¼ etoposide. aTwo of the patients with TBI did only receive 2 Gy.

Table 2 Patients with offspring

Diagnosis Date of birth Date of HSCT Conditioning regimen Details

Female patients (n ¼ 3) ES 1982 2002 BU 12.8 mg/kg MEL 140 mg/m2 Healthy baby, born at term 2006 MDS 1983 2001 THIO 15 mg/kg FLU 160 mg/m2 Healthy boy, born at term 2007 amenorrhoea after birth SAA 1985 2003 CY 200 mg/kg Healthy baby, born at term 2004

Male patients (n ¼ 2) SAA 1987 2003 CY 200 mg/kg 3 Healthy babies, all born at term, 2005, 2006, 2007 SAA 1988 2004 CY 200 mg/kg Healthy girl, born at term 2010

Abbreviations: ES ¼ Ewing sarcoma; FLU ¼ fludarabine; HSCT ¼ haematopoeitic stem cell transplantation; MDS ¼ myelodysplastic syndrome; MEL ¼ melphalan; SAA ¼ severe aplastic anaemia; THIO ¼ thiotepa. and BU versus no BU (OR 47.4; 95% CI, 5.4 to 418.1) for impaired fertility: azoospermia (n ¼ 7), hormone repla- significantly increased the risk of infertility. No association cement therapy (n ¼ 10), hormonal analysis (n ¼ 101; with infertility was found for CY and VP-16. FSH 415 IU/L, n ¼ 66; LH415 IU/L, n ¼ 16; testosterone o2 ng/mL, n ¼ 38). Testicular volumes were measured in 99 male participants by the local centre conducting the Males treatment. Microorchidism was seen in 50 of these patients. A total of 131 of the 190 males (69%) with data on fertility Analyses of testicular volume showed no statistically were considered to be infertile based on one or more criteria significant correlations with FSH (r ¼À0.118) or LH

Bone Marrow Transplantation Fertility after HSCT in childhood and adolescence A Borgmann et al 274 Table 3 Fertility outcomes and hormone analyses for participants without hormone substitution

Risk factors Women Men

Median (range) Median (range) Median (range) Median (range) FSH (IU/L), n LH (IU/L), n FSH (IU/L),n LH (IU/L), n

HSCT at age 1–12 years 6.8 (0.5–103.3), 35 4.0 (0.1–87.0), 35 4.7 (0.2–95.0), 82 2.8 (0.01–191.0), 85 HSCT at age X13 years 26.9 (0.1–107.0), 29 12.4 (.01–111.0), 28 14.9 (0.4–65.7), 90 7.6 (0.02–46.0), 90 P-value 0.12 0.007 o0.001 o0.001

TBI 6.7 (1.1–67.5), 16 6.3 (0.6–38.0), 16 15.4 (0.56–65.7), 80 7.0 (0.1–46.0), 80 Versus no TBI 13.3 (0.1–107.0), 48 7.7 (0.01–111.0), 47 6.2 (0.2–95.0), 92 4.9 (0.02–191.0), 95 P-value 0.33 0.93 o0.001 0.04

BU 44.6 (0.5–107.0), 24 20.4 (0.1–111.0), 23 6.9 (0.2–95.0), 64 4.8 (0.02–191.0), 66 Versus no BU 5.7 (0.1–67.5), 40 4.7 (0.01–38.0), 40 12.1 (0.6–65.7), 108 6.4 (0.1–46.0), 109 P-value o0.001 0.004 0.03 0.25

Abbreviations: FSH ¼ follicle-stimulating hormone; LH ¼ luteinizing hormone; HSCT ¼ haematopoietic stem cell transplantation.

Table 4 Hormone analysis in patients with non-myeloablative conditioning regime (TBI/TLIo6 Gy or BU 2 mg/kg) Diagnosis Conditioning regime LH (IU/L) FSH (IU/L) Oestradiol (pg/mL) Testosteron (nmol/L)

Female patients Wegener’s granulomatosis TBI 2 Gy/TLI 2 Gy; FLU 90 mg/m2 4 9 59 — HbSS TLI 2 Gy; FLU 180 mg/m2, MEL 140 mg/m2 12 4 379 — HbSS TLI 2 Gy; FLU 180 mg/m2; MEL 140 mg/m2 81447— HbSS TLI 2 Gy; FLU 180 mg/m2 MEL 140 mg/m2 51065— SAA TBI 5,4 Gy; Cy 200 mg/kg 126 192 52 — MDS TLI 2Gy; FLU 180 mg/m2; MEL 140 mg/m2 21 38 290 — FA BU 2 mg/kg; FLU 180 mg/m2 87 103 4 —

Male patients SAA TLI 5 Gy; FLU 160 mg/m2; CY 120 mg/kg 6 9 — 6 CVID TLI 2Gy; FLU 180 mg/m2; Mel140 mg/m2 48 — 3 MDS TBI 2 Gy; FLU 160 mg/m2; THIO 15 mg/kg 8 19 21 14 XLP TLI 5 Gy; FLU 180 mg/m2; MEL 140 mg/m2 826— 1 FA TBI 4 Gy; FLU 150 mg/m2 20 40 — 25 MDS BU 2 mg/kg; FLU 180 mg/m2 55 — 9 FA BU 2 mg/kg; FLU 180 mg/m2 23 — 3 FA BU 2 mg/kg; FLU 180 mg/m2 621— 1 FA BU 2 mg/kg; FLU 180 mg/m2 o11 — o1 FA BU 2 mg/kg; FLU 180 mg/m2 11 27 — 14 FA BU 2 mg/kg; FLU 180 mg/m2 13 16 — 8 FA BU 2 mg/kg; FLU 180 mg/m2; CY 40 mg/kg 8 11 — 8

Abbreviations: CVID ¼ common variable immunodeﬁciency; FA ¼ Fanconi anaemia; FLU ¼ ﬂudarabine; FSH ¼ follicle-stimulating hormone; HbSS ¼ homozygous sickle cell anaemia; LH ¼ luteinizing hormone; MDS ¼ myelodysplastic syndrome; MEL ¼ melphalan; SAA ¼ severe aplastic anaemia; THIO ¼ thiotepa; XLP ¼ x-linked lymphoproliferative disease.

(r ¼ 0.016). There was a weak correlation of testicular participants who underwent TBI (76 of 91, 84%) than volume with testosterone (r ¼ 0.21; P ¼ 0.02). among those not receiving TBI (55 of 99, 56%; Po0.001). Males aged 1–12 years at the time of HSCT had Three males received TLI of 2 Gy, 5 Gy and 5 Gy. significant lower medians of LH and of FSH, which were Hypergonadotropic hypogonadism was present in one both within the normal ranges, compared with males aged participant in this group. Table 4 gives an overview on 13 years or older at HSCT (Table 3). Comparing the age 12 male patients with non-myeloablative therapy. groups we found—in contrast to the female participants— BU was given at a median dose of 16 mg/kg (range that suspected infertility was less frequent in males who 2–20 mg/kg). In the group of male participants treated received HSCT treatment at the age of 13 or later (60 of with BU, the median LH was lower compared with 100, 60%) than in those in whom treatment started at the those without BU, but the difference was not statistically ages of 1–12 (71 of 90, 79%). significant. FSH values were significantly higher in the In all, 95 males received TBI at a median dose of 12.3 Gy participants who did not receive BU treatment. There were (range 2.0–14.4 Gy). Male participants who received TBI fewer participants with suspected infertility among male had significantly higher FSH values than those not patients who received BU therapy (43 of 69, 62%) than receiving TBI (Po0.001). LH values were also raised in among patients who did not (88 of 121, 73%; P ¼ 0.136). the group of TBI patients (P ¼ 0.04; Table 3). Suspected In multivariable logistic regression analyses, TBI com- infertility was significantly more frequent among male pared with no TBI (OR 7.7; 95% CI, 2.3 to 25.4) and

Bone Marrow Transplantation Fertility after HSCT in childhood and adolescence A Borgmann et al 275 pre-puberty compared with puberty (OR 0.4; 95% CI, 0.2 the risk for infertility, which is inconsistent with findings of to 0.8) were found to significantly increase the risk of other recent studies.21 infertility. BU, CY and VP16 were not associated with The fact that TBI was a significant risk factor for infertility in male subjects. infertility in males is not surprising given that impaired sperm production in the form of temporary oligospermia occurs after radiotherapy at dosages as low as 0.1 Gy. This Discussion azoospermia may resolve over a period of years. Doses of 1.5 Gy or more can lead to long-term cessation of sperm The present study on the topic—the largest such investiga- production and doses above 4 Gy to irreversible azoosper- tion conducted to date in paediatric HSCT recipients— mia.10 Ovarian damage occurred after a TBI dose of 12 Gy included data on treatment and fertility from 344 patients in girls over the age of 10 years in virtually all cases, from seven paediatric HSCT centres in Europe. After a whereas in girls o10 years only in approximately a half.2 median follow-up period of 6 years from HSCT, the infertility rate in the study group was 75% overall, with Conclusion rates of 83% in the female participants and 69% in the male participants. The follow-up period of 6 years after the More than two-third of former paediatric patients who had start of treatment does not seem to be too short, in view of received allogeneic HSCT showed signs of impaired fertility. the fact that testicular recovery occurs in the initial years Significant risk factors were TBI for males and BU for after HSCT and that the sharpest decline in ovarian reserve females. Our results emphasise the need for comprehensive takes place immediately after treatment.19,20 counselling of patients undergoing HSCT, particularly those Seven children were born to the overall group, all at term receiving TBI- or busulfan based preparative regimens and and healthy. None of the female participants who became their parents regarding fertility preserving measures. pregnant or male patients who fathered a child had been treated with TBI before HSCT. Pregnancies after HSCT have to date been regarded as a rarity. If a woman became Conflict of interest pregnant, however, it has been recommended that she should receive close monitoring, as higher rates of The authors declare no conflict of interest. miscarriage and premature birth have been reported. Congenital abnormalities have not been found to occur References more frequently in these cases.3 Impaired fertility is a well-known side effect after HSCT 1 European Group for Blood and Marrow Transplanta- in childhood and adolescence but studies in the field are tion. Statistical Summary of EBMT Database, March 2005. often limited by small numbers of patients in the various Available at: http://www.ebmt.org/4Registry/registry5.html groups.21–23 A recent study on the recovery of spermato- (accessed May 2008). genesis after HSCT reported that spermatozoa were found 2 Mertens AC, Ramsay NK, Kouris S, Neglia JP. Patterns of in sperm fluid analyses in 58 of 217 males (27%) after a gonadal dysfunction following bone marrow transplantation. 24 Bone Marrow Transplant 1998; 22: 345–350. median follow-up period of 4.5 years. A recent review of 3 Salooja N, Szydlo RM, Socie G, Rio B, Chatterjee R, paediatric HSCT reported that impaired fertility was Ljungman P et al. Pregnancy outcomes after peripheral present in nearly all females treated with conditioning blood or bone marrow transplantation: a retrospective survey. protocols including BU. CY-induced ovarian failure was Lancet 2001; 358: 271–276. also reported in female survivors after HSCT, although to a 4 Bines J, Oleske DM, Cobleigh MA. Ovarian function in lesser extent.2 premenopausal women treated with adjuvant chemotherapy Examining risk factors for infertility in the present study, for breast cancer. J Clin Oncol 1996; 14: 1718–1729. TBI in particular appeared to be gonadotoxic for males. 5 Lutchman Singh K, Davies M, Chatterjee R. 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