does ifosfamide affect gonadal function?

Pediatr Blood Cancer 2008;50:347–351

Does Ifosfamide Affect Gonadal Function?

Denise Williams, MB, FRCP, FRCPCH,1{* P.M Crofton, MA, PhD, MRCPath,2 and Gill Levitt, BSc, MB, MRCP, FRCPCH3

INTRODUCTION

Direct gonadal damage is known to occur following radio-

therapy to the spine or pelvic area and as a result of chemo-

therapeutic agents, such as cyclophosphamide, procarbazine,

nitrogen mustard, melphalan and busulphan [1–4]. The dosage

causing infertility is unknown and may differ between the sexes and

the age at treatment. Ifosfamide, as a structural isomer of cyclo-

phosphamide, is thought likely to cause gonadal dysfunction, but as

yet there is little published evidence.

We have evaluated gonadal function of patients enrolled in

protocols for treatment of Ewing’s sarcoma and soft tissue sarcoma

in the 1980–1990s, containing ifosfamide as the only potential

gonadotoxic agent. Assessment included clinical evaluation of

pubertal development, menstrual history in females and semen

analysis in males, and measurement of follicle stimulating hormone

(FSH), leuteinizing hormone (LH), sex steroids, inhibin B and anti-

Mullerian hormone (AMH). Elevation of gonadotrophins reflects a

combination of hypothalamic–pituitary drive and gonadal hormone

feedback [5]. In males, inhibin B secreted by testicular sertoli

cells, is a marker of spermatogenesis [6–9]. In females, inhibin B

produced by granulosa cells [10] decreases during reproductive

ageing [11–14]. AMH is also produced by granulosa cells [15], is a

marker of the number of antral follicles during the early follicular

phase of the menstrual cycle, and declines during ovarian aging,

reflecting the loss of ovarian follicular reserve [16–19].

METHODS

Patient Population and Protocols

Twenty-two United Kingdom Children’s Cancer Study Group

(UKCCSG) centres agreed to participate in the study. One hundred

sixty-one eligible patients (95 male and 66 female) were identified.

All patients were event-free survivors for more than 2 years,

were post pubertal and greater than 15 years of age at the time of the

study. Patients who had received gonadal or cranial/lower spinal

radiation and/or cyclophosphamide doses>2.5g/m2 were excluded.

Females on the oral contraceptive pill (OCP) were excluded unless

they were prepared to come off the OCP for 6 weeks prior to blood

testing. Multicentre research ethical permission was obtained for the

study. Patients had all been treated on one of the ifosfamide

containing protocols [20–22] detailed in Supplemental Figure 1.

Patient Assessment

For male and female patients, this was based on enquiry, clinical

assessment [23,24] and laboratory results as outlined in Supple-

mental Table I.

Biochemical Assays

All hormonal analyses were performed in duplicate in a single

laboratory. Details of assays and hormonal reference ranges used are

given as Supplemental Data 1.

Statistics

Data were expressed as medians and ranges. Differences

between groups were assessed using the Mann–Whitney U-test.

Relations between variables were explored using Spearman rank

correlation.

Background. Gonadal dysfunction and infertility are potentiallate effects of cancer therapy. Ifosfamide, an alkylating agentstructurally related to cyclophosphamide, is thought to causegonadal dysfunction, though there is little published evidence.Procedure. Patients treated on sarcoma protocols containingifosfamide as the only potential gonadotoxic agent, were evaluated,assessing pubertal development, menstrual history in the females andsemen analysis in males. Biochemical evaluation included measure-ment of gonadotrophins, inhibin B and anti-mullerian hormone(AMH). Results. All 32 males progressed normally through puberty.No gonadal dysfunction was seen at a total ifosfamide dose of<60 g/m2. In those with a dose >60 g/m2, two-thirds of those whounderwent semen analysis were subfertile, 31% had elevated FSH

and 50% showed decreased inhibin B supporting evidence of germcell failure. All 13 females progressed through puberty normally andhad regular menses. Biochemical results were in line with publisheddata except for AMH levels, which were lower compared with anage-matched reference group. Nine patients not recruited into thestudy were known to have had 11 live births. Conclusions. Malesappear more susceptible than females to ifosfamide gonadotoxicity.There may be a dose in males below which the risk of subfertility islow. In females there is preliminary evidence of reduction in ovarianreserve as measured by AMH levels, which may potentially lead toan early menopause and a reduction in the window of fertility.Pediatr Blood Cancer 2008;50:347–351. � 2007 Wiley-Liss, Inc.

Key words: gonadal function; ifosfamide; infertility; late effect of chemotherapy

� 2007 Wiley-Liss, Inc.DOI 10.1002/pbc.21323

——————This article contains Supplementary Material available at http://www.

interscience.wiley.com/jpages/1545-5009/suppmat.

1Department of Paediatric Oncology, Addenbrooke’s Hospital,

Cambridge University Hospitals NHS Foundation Trust, Cambridge,

UK; 2Department of Paediatric Biochemistry, Royal Hospital for Sick

Children, Edinburgh, UK; 3Department of Paediatric Oncology, The

Hospital for Sick Children, Great Ormond St., London, UK

Submitted on behalf of the Late Effects Group of the United Kingdom

Children’s Cancer and Leukaemia Group (CCLG).

{Consultant Paediatric Oncologist.

*Correspondence to: Denise Williams, Department of Paediatric

Oncology, Addenbrooke’s Hospital, Cambridge University Hospitals

NHS Foundation Trust, Hills Road, Cambridge CB2 2QQ, UK.

E-mail: [email protected]

Received 30 November 2006; Accepted 26 June 2007

RESULTS

One hundred sixty-one patients were eligible for the study. Only

45 completed the study, 32/95 males 30%, 13/66 females 20%.

20 patients were lost to follow-up, and 14 refused: 5 because they

had live births, 5 were pregnant at time of study and 4 because they

were on the OCP. 2 completed questionnaires only. The patient

characteristics of those who completed the study are shown in

Table I. The characteristics of those eligible patients who did not

enter the study are shown in Supplemental Table II.

Males

Thirty-two males received a median dose of ifosfamide 92 g/m2

with a skewed bimodal distribution. Nine patients treated on the

Ewing sarcoma study, ET-2 [20] had also received cyclophospha-

mide 0.3–2.4 g/m2 during radiotherapy (Supplemental Table III).

Patients were divided into two ifosfamide dose ranges, based on the

bimodal distribution of doses: low-dose (<60 g/m2, n¼ 6) and high-

dose (>60 g/m2, n¼ 26).

No patient admitted any sexual dysfunction and 2/32 had

fathered children. All were post-pubertal G4/5. Twenty-seven males

had testicular volumes in excess of 12 ml with a median of 20 ml

(range 5–25 ml). Five males had testicular volumes less the 12 ml

and although there was no overall correlation between testicular size

and ifosfamide dose (P¼ 0.23) and no significant difference in

testicular size between the low- and high-dose groups (P¼ 0.32), all

the males with small (<12 ml) testes were in the high-dose group

having received a median dose of ifosfamide of 96 g/m2 (range 94–

114.5 g/m2). The male with 5 ml testes had an elevated FSH and was

azoospermic on sperm analysis.

There were no overall correlations between hormone levels and

ifosfamide dose (P> 0.36) but there was evidence of a dose

threshold effect. Table II shows hormone results in males treated

with low- or high-dose ifosfamide, compared with adult male

reference ranges.

In the high-dose group, 8/26 had high FSH levels (>10 U/L), 13

had reduced inhibin B (<80 pg/ml), 2 had increased LH (>8.4 U/L)

and 1 had decreased testosterone (<8 nmol/L). FSH was signi-

ficantly correlated with age at treatment (r¼þ0.39, P¼ 0.049) but

inhibin B showed no significant trend with age at treatment

(r¼�0.21, P¼ 0.26). No abnormal values of LH, FSH or

testosterone were observed in the low-dose group. One patient

from this group had a low inhibin B but had nevertheless fathered a

child.

Sperm counts were obtained in 13 males with a median

sperm count 11� 106/ml (range 0–125� 106/ml). 8/11 males in

the high-dose group had low sperm counts <20� 106/ml, of whom

3 were azoospermic. Sperm counts were available in only two

males in the low-dose group: both had sperm counts >20� 106/ml.

FSH had a strong negative (r¼�0.80, P< 0.001) and inhibin B a

positive relationship (r¼þ0.67, P¼ 0.013) with sperm count

(Table III).

Females

The thirteen females were treated at a median age of 12.1 years

(Table I). They were Tanner stage 4/5 at the time of study and

had regular menses. Median age of menarche was 13.0 years

(range 11.5–17.0 years). Four were post menarche at the time of

treatment. None of the females reported menopausal symptoms.

One patient had had a normal live birth.

This female cohort had received a median dose of ifosfamide of

59.4 g/m2 (range 27–90 g/m2), significantly lower than that received

by the male cohort (P¼ 0.001). Two patients treated for Ewing’s

tumours on the ET-2 study [20] had also received cyclophospha-

mide, 1.4 and 1.5 g/m2 (Supplemental Table IV). Nine additional

patients, who did not take part in the study, were known to have had

at least 11 live births, all at an age of less than 30 years. 1 required

clomiphene stimulation. They had received a median ifosfamide

dose of 85.7 g/m2 (range 36–114 g/m2). There were no reports of

abnormalities in the offspring.

Table IV shows hormone results in the female group. The single

woman with an LH >5.0 U/L (11.1 U/L) had received a cumulative

ifosfamide dose of 84 g/m2. She had a baby in the year of the study,

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE I. Patient Characteristics

Males Females

Number 32 13

Ewings:soft tissue sarcoma 27:5 11:2

Age at diagnosis (years)a 11.8 (5.4–21.3) 12.1 (3.6–15.6)

Age at follow-up (years)a 20.8 (16.0–29.3) 21.6 (18.8–26.6)

Follow-up interval (years)a 9.7 (3.3–12.6) 10.1 (2.9–15.6)

Total ifosfamide dose (g/m2)a 92.0 (36.0–114.5) 59.4 (27.0–90.0)

aData expressed as median (range).

TABLE II. Hormone Results in Male Subjects Treated With Low-Dose (<60 g/m2) or High-Dose (>60 g/m2) Ifosfamide

Test Reference range Low dosea (n¼ 6) High dosea (n¼ 26) P-value*

LH (U/L) 1.0–8.4 2.3 (1.3–4.2) 4.7 (1.7–12.1) 0.021

FSH (U/L) 1.0–10.0 2.4 (0.4–5.6) 5.7 (0.8–20.8) 0.026

Testosterone (nmol/L) 8–35 19.7 (11.8–25.9) 20.9 (6.4–41.4) 0.44

Inhibin B (pg/ml) >80 176 (42–346) 78 (4–427) 0.074

aData are expressed as median (range); *Low dose versus high dose.

348 Williams et al.

which may have affected this result. Only one patient had an

elevated oestradiol, perhaps signifying early follicle recruitment as

a sign of decreased ovarian reserve. However this patient had an

inhibin B and AMH within the age matched reference range. The

median AMH level in the study group was lower than in the

reference age-matched subgroup. Four of 13 females had AMH

levels below the range seen in the reference subgroup. These four

females varied widely in age at diagnosis (range 3.6–15.6 years),

were treated on different chemotherapy protocols and received a

range of ifosfamide doses from 18 to 84 g/m2 There was no

correlation between the dose of ifosfamide and LH, FSH, inhibin B

or AMH levels (P> 0.1). Oestradiol was positively correlated with

ifosfamide dose (r¼þ0.79, P¼ 0.001).

DISCUSSION

The gonadotoxic effects of alkylating agents have been known

for decades, the main risk factors being male gender and increased

cumulative dose. Low inhibin B and high FSH have been reported in

adult men treated with chemotherapy for haematological malig-

nancies [25] and in post-pubertal male survivors of childhood cancer

treated with regimens containing cyclophosphamide [26].

Unfortunately, there are scant data on the effect of individual

drugs, the effect of varying dosages or longitudinal information to

determine whether gonadal dysfunction might be temporary or

permanent. This lack of data is due to the complexity of assessing

combination chemotherapy containing more than one gonadotoxic

agent, the lack of prospective studies and of reliable indicators of

future fertility. Long-term follow-up studies often suffer from low

recruitment [27] as seen in our study. This may be due to loss of

patients to follow-up, inappropriate timing of the studies for a

particular individual or perhaps, a reluctance by either patient or

treating clinician to think about the impact of treatment often given

many years before.

We have attempted to look at the effect of ifosfamide at various

cumulative dosages in both males and females, to clarify its

gonadotoxicity profile. A few patients had also received cyclo-

phosphamide at low dosages that have not been reported to be

associated with gonadotoxicity and had no effect on the hormonal

results in this study (Supplemental Tables III and IV).

All 32 male participants progressed normally through puberty. In

males, there appeared to be a dose threshold, with no biochemical

evidence of gonadal dysfunction or infertility in albeit a very small

group of patients receiving less than 60 g/m2. Sperm counts were

requested as part of the study but were available for less than half of

the participants, for various reasons including a reluctance to know

such a result at the particular time it was requested for some and the

sensitive nature of this investigation for others. In those in whom

sperm counts were available, FSH showed a strong negative

correlation and inhibin B a positive correlation with sperm count, as

has been shown by others [7–9] confirming the value of these

hormones as surrogate markers of spermatogenesis and fertility.

Sperm analysis in the high-dose ifosfamide group (>60 g/m2),

showed 73% to be subfertile and 27% azoospermic. In the full cohort

of males treated with these higher doses, 31% had increased FSH

and 50% had decreased inhibin B, supporting evidence of germ cell

failure. All but one of the males in this high-dose group had normal

testosterone and all but two had normal LH, indicating relatively

preserved Leydig cell function. Among males treated with higher

cumulative doses of ifosfamide, there was no convincing evidence

that older males were more at risk of adverse effects on fertility

than younger boys, though numbers were too small to draw firm

conclusions.

Similar findings were reported in a questionnaire-based study of

male osteosarcoma patients [27] that concluded ifosfamide was a

major cause of infertility and reported a dose dependent relationship

with higher doses of ifosfamide increasing the risk of infertility.

However, all patients in that study had also received cisplatin,

known to be gonadotoxic [28] in addition to ifosfamide and more

than half of the patients who did not receive ifosfamide were also

azoospermic. Of the 96 recruited subjects only 26 provided a

sperm sample and 5 were studied with biochemical markers.

Another study of 33 young male survivors of childhood cancer, of

whom 8 had received cyclophosphamide-based and 25 had received

ifosfamide-based regimens, confirmed the previously reported

gonadotoxic effects of cyclophosphamide [29]. In the group treated

with ifosfamide, although mean sperm counts, FSH and inhibin B

were within the normal range, standard deviations were wide

implying that some patients had impaired fertility. There was no

relation with ifosfamide dose but rapid ifosfamide infusion


TABLE III. FSH and Inhibin B in Male Subjects With Low or Normal Sperm Counts

Test Sperm count (<20� 106/ml) Sperm count (>20� 106/ml) P-value*

FSH (U/L) 12.1 (4.4–18.9) 3.8 (0.7–5.4) 0.003

Inhibin B (pg/ml) 40 (4–89) 171 (66–199) 0.006

Data are expressed as median (range). *Low versus normal sperm count.

TABLE IV. Hormone Results in Female Subjects

Test Study groupa Reference groupaNumber of study group with

abnormal results

LH (U/L) 4.2 (2.0–11.1) 4.4 (1.6–9.3) 1/13

FSH (U/L) 5.6 (2.6–7.9) 4.4 (2.4–9.3) 0/13

Oestradiol (pmol/L) 161 (43–457) 151 (64–404) 1/13 (low), 1/13 (high)

Inhibin B (pg/ml) 80 (21–113) 112 (12–213) 0/13

AMH (pmol/L)b 12.2 (5.1–31.6) 25 (11–40) 4/13

aData are expressed as median (range); bTo convert pmol/L AMH to mg/L divide by 7.14.

Does Ifosfamide Affect Gonadal Function? 349

protocols were associated with higher FSH levels than slow

infusions. Our study adds to these previous studies supporting the

conclusion that ifosfamide has an adverse effect on fertility in males.

The different results in terms of a dose threshold for infertility may

simply be due to small numbers in each study.

Conclusions from available literature for females treated with

ifosfamide have been non-definitive because of low numbers. Two

papers report that patients treated for osteogenic sarcoma with

chemotherapy protocols involving ifosfamide showed evidence

of ovarian dysfunction requiring hormone replacement therapy

[30,31]. In both studies, ifosfamide was used in combination with

cisplatin or cyclophosphamide, both of which have been shown to be

associated with gonadotoxicity. There are also reports showing the

transient effect of chemotherapy with variable return of ovarian

function [4,31].

Poor recruitment to our study hampers interpretation of our

results for females. In addition, the female cohort received a lower

median dose of ifosfamide, 59.4 g/m2 compared to 92 g/m2 in the

male cohort. All our patients had passed through puberty normally

and had regular menstruation without requiring hormone replace-

ment therapy. One patient had evidence of pubertal delay with a

menarche at age 17 years, thought to be due to her underlying

diagnosis and protracted chemotherapy. Menarche commenced

after recovery from chemotherapy.

The hormone results in our cohort are in line with published data

on normally cycling women in the follicular phase, except for AMH.

AMH is age dependent in pre-menopausal women and declines with

age as follicle numbers fall [17]. Median AMH in our study group

was lower than in the age-matched reference group and was closer to

that reported for older women aged 30–35 years [17]. This is

consistent with depletion of follicle reserve, which may result in a

premature menopause. One previous study of 10 adult female

survivors of childhood cancer with regular menstrual cycles has also

reported lower AMH levels compared with age-matched controls,

although no details of chemotherapeutic regimens were provided

[16]. It was gratifying to know that some of our patients from the

original cohort have had live births, despite receiving high

ifosfamide dose (more than 60 g/m2). However, these were all at

an age of<30 years, and an early menopause may still be an issue for

these patients.

Though our data cannot be conclusive in view of the small

numbers, we have shown that males appear more susceptible than

females to ifosfamide related gonadal damage, although there

may be a dose threshold in males below which the risk of subfertility

is low. It was reassuring to identify patients who had had normal

live births, despite high-dose ifosfamide. However, there does

appear to be some evidence of reduced ovarian reserve as measured

by serum AMH levels, which may lead to an early menopause and a

reduction in the window of fertility for these females. The number of

females recruited in this study was small so it was not possible to

discern any dose effect. However, overall, our female cohort had

received a lower cumulative ifosfamide dose compared with the

males.

With the knowledge that fertility preservation techniques may

have a realistic chance of offering these patients the opportunity of

having their own offspring in the future, we hope that there will be a

greater enthusiasm for adding prospective long-term follow-up

questions to treatment protocols, allowing longitudinal studies to

accurately inform both new patients and survivors of subfertility

risks and options for management.

ACKNOWLEDGMENT

The authors would like to thank CLIC Sargent, the children’s

cancer charity, for their financial support for the study. They would

also like to thank the clinicians in all the UKCCSG centres, who

recruited patients into this study, the UKCCSG data centre,

particularly Caroline Ellershaw and Carolyn Douglas, and acknowl-

edge the support given to the data centre by Cancer Research UK.

We gratefully acknowledge the technical expertise of Nancy Evans

in carrying out the hormone measurements for this study.

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Does Ifosfamide Affect Gonadal Function? 351

does ifosfamide affect gonadal function?

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