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Hum. Reprod. Advance Access published online on January 23, 2008
Human Reproduction, doi:10.1093/humrep/dem392
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Anti-müllerian hormone as a marker of ovarian function in women after chemotherapy and radiotherapy for haematological malignancies

S. Lie Fong1,4, P.J. Lugtenburg2, I. Schipper1, A.P.N. Themmen3, F.H. de Jong3, P. Sonneveld2 and J.S.E. Laven1

1 Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus Medical Centre, Room Hs-422K, PO Box 2040, 3000 CA Rotterdam, the Netherlands 2 Department of Haematology, Erasmus Medical Centre, Rotterdam, the Netherlands 3 Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands

4 Correspondence address. Tel: +31-10-70-33371; E-mail: s.liefong{at}erasmusmc.nl


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
BACKGROUND: In female cancer survivors, the accelerated loss of primordial follicles as a result of gonadal damage may lead to premature ovarian failure (POF). However, the extent of the damage is unpredictable. Anti-Müllerian hormone (AMH) constitutes a sensitive marker of ovarian reserve. Serum AMH levels were measured to assess sub-clinical ovarian damage in patients treated with gonadotoxic therapy.

METHODS: In 25 patients with haematological malignancies, serum AMH concentrations were measured prior to and after cancer therapy and were compared with normo-ovulatory controls.

RESULTS: In all patients, AMH concentrations were lower than controls prior to treatment. Thirteen patients were treated with multi-drug chemotherapy. Although in most patients treated with chemotherapy menstrual cyclicity was restored, median serum AMH levels were lower than in controls. Twelve patients had stem cell transplantation (SCT) after total body irradiation. They all developed POF and their serum AMH concentrations were undetectable.

CONCLUSIONS: Female cancer survivors treated with SCT all developed POF. Hence, in these patients fertility preservation should be considered. In patients treated with chemotherapy, ovarian reserve seems to be compromised as well.

Key words: Anti-Müllerian hormone/female cancer survivor/ovarian reserve


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The number of patients surviving cancer is increasing, hence long-term effects of chemotherapy and/or radiotherapy are becoming more apparent (Howell and Shalet, 1998Go; McVie, 1999Go). The extent of gonadal damage depends on the treatment modality, the dose received and patients’ age. Alkylating agents, such as cyclophosphamide (CY) and procarbazine, as well as radiotherapy are highly gonadotoxic. However, non-gonadotoxic drugs in multi-drug regimens may have a cumulative toxic effect on reproductive function (Brougham and Wallace, 2005Go). So far, long-term follow-up studies have assessed ovarian function after cancer treatment using parameters such as FSH serum levels or clinical end-points such as cycle length or pregnancy rates (Whitehead et al., 1983Go; Byrne et al., 1992Go; Clark et al., 1995Go; Bines et al., 1996Go; Mackie et al., 1996Go; Bath et al., 2003Go; Behringer et al., 2005Go). However, a recent report on gonadal function in childhood cancer survivors showed that, notwithstanding regular menstrual cycles, in patients treated with chemotherapy and cranial radiotherapy, ovarian reserve was compromised as assessed by serum anti-Müllerian hormone (AMH) concentrations (Bath et al., 2003Go). Moreover, other studies showed that female cancer survivors with regular menses and normal serum FSH levels had significantly smaller ovaries along with a lower antral follicle count as compared to age-matched controls (Larsen et al., 2003aGo,bGo). These observations indicate that parameters such as cycle length and FSH serum levels are not accurate markers of ovarian function. Serum AMH levels, antral follicle count and ovarian volume appear to be more reliable predictors (Bath et al., 2003Go; Larsen et al., 2003aGo).

Recently, it was shown that serum AMH levels may constitute a valuable marker of ovarian reserve (Visser and Themmen, 2005Go). Clinical trials indicated that serum AMH concentrations correlated well with antral follicle count and age. With increasing age, the number of primordial, preantral and small antral follicles declines and concomitantly serum AMH levels decrease. Moreover, in ageing females, AMH levels were decreased, while other factors associated with perimenopausal status, such as early follicular phase FSH, inhibin B or estradiol (E2) serum levels did not change significantly (de Vet et al., 2002Go; van Rooij et al., 2005Go). Finally, AMH levels are unaffected by cyclic variations or the use of oral contraceptive pills (OCP) (Cook et al., 2000Go; Fanchin et al., 2005Go; Hehenkamp et al., 2006Go; Somunkiran et al., 2007Go). Currently, serum AMH levels seem to represent the most reliable marker to determine ovarian reserve.

In the current study, serum AMH concentrations were measured in order to assess the ovarian reserve in women previously treated with gonadotoxic agents for haematological malignancies.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Approval for the study was obtained from the local medical ethics review board. Written informed consent was obtained from each participant.

Premenopausal women from whom serum samples were taken before and after treatment for haematological malignancy at the Erasmus MC University Hospital between January 1995 and December 2004 were eligible.

Women without a history of cancer and with a regular menstrual cycle were recruited as controls. Inclusion criteria were age between 20 and 35 years, BMI between 19 and 26 kg/m2 and normal menstrual cycle length between 26 and 31 days. These women had participated in previous studies (de Vet et al., 2002Go; Hohmann et al., 2003Go). In addition, they were healthy and all proven fertile. They did not have any actual or previous endocrine disease, they used neither medication, nor OCPs, nor any hormonal treatment.

Study design
Prior to treatment as well as during follow-up, blood samples were drawn and serum was stored at –20°C. Clinical screening at follow-up included recording of obstetric and cycle history, medication use and OCP use (Imani et al., 1998Go). Ultrasound scanning included measurement of ovarian volume and total number of follicles and was performed by a single investigator (S.L.F.). In patients with regular menstrual cycles, screening was performed in the early follicular phase (between cycle day 2 and 5). In patients using OCPs, screening was planned at the last day of the pill-free interval (van Heusden et al., 2002Go). Endocrine screening included assays of serum gonadotrophins, E2, inhibin B and AMH. LH and FSH levels were measured using a luminescence based immuno assay (Immulite, Diagnostic Products Corp., Los Angeles, CA, USA). A radioimmunoassay was used to assess E2 serum levels (Diagnostic Products Corp.). Intra- and inter-assay coefficients of variation were <5 and 15% for LH, <3 and 8% for FSH and <5 and 7% for E2. Serum Inhibin B levels were determined using an enzyme-linked immunoassay as described earlier (Oxford Bio Innovation, Oxford, UK) (Groome et al., 1996Go). Intra- and inter-assay coefficients of variation were <9 and 15%. Serum AMH levels were measured by double-antibody enzyme-linked immunosorbent assay (ELISA) in serum samples taken before and after treatment as described before (Al Qahtani et al., 2005Go). Intra- and interassay coefficients of variation were 3.6 and 4.0%, respectively. AMH immunoreactivity in serum samples was stable for several days at room temperature and after repeated freeze–thaw cycles (Kevenaar et al., 2006Go). Values were adjusted to allow comparison with AMH levels in controls which were assayed with an ELISA (Immunotech-Coulter, Marseilles, France) (de Vet et al., 2002Go).

Statistics
To assess selection bias, general patient characteristics were compared between enrolled patients and drop-outs, using non-parametric tests. Similarly, non-parametric tests were performed to compare demographic, endocrine, cycle and treatment characteristics in patient subgroups. Serum AMH levels were compared using univariate analysis of covariance, adjusting for age differences. The decline in AMH levels in controls was calculated according to standard formulas for prediction intervals in linear regression analysis, reflecting fifth, 50th and 95th percentiles. The formula: AMH*exp(3.47–0.102*age) reflects the mean decline in AMH levels in controls, adjusting for increasing age. The formula: AMH*exp(3.47–0.102*age) ± 1.48*{surd} (1.013+((age–30.48)/38.45)2)) reflects the 5th and 95th prediction intervals for decline of AMH levels, with adjustment for increasing age (de Vet et al., 2002Go). The interval between the first and last visit was calculated using the formula: (date of first visit–date of last visit)/365 days. The remaining fraction of ovarian function after cancer therapy was calculated according to a formula comparing the remaining AMH in serum to the AMH serum level at the first visit, controlling for the interval between first and last visit: (AMH at last visit/AMH at first visit)*exp(1/interval). Statistical analysis was performed using Statistical Package for Social Sciences 12.0 (SPSS Inc, Chicago, IL). A P-value <0.05 indicates statistical significance.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
For 37 patients, pretreatment serum samples were available. All patients were treated with chemotherapy and/or radiotherapy according to HOVON (Dutch haemato-oncology association) protocols (http://www.hovon.nl). Diagnosis, treatment protocol and cumulative doses of chemotherapy and irradiation were recorded for each patient (Table I). From 12 women, serum was not obtained post-treatment. Two of these 12 had died from their disease. Participation was refused by 4 patients with severe complaints attributable to their treatment. The remaining 6 patients refused for unknown reasons. Among the group of drop-outs, a significantly higher number of OCP users was observed. In those enrolled, an increased incidence of oligomenorrhoea before treatment was found (P< 0.001). Finally, 25 women were eligible for analysis. These patients were divided into subgroups according to their treatment, i.e. multi-drug chemotherapy (group A, n= 13) or stem cell transplantation (SCT) after total body irradiation (TBI) and high-dose CY (group B, n= 12). Group C consisted of 42 control women. Patient numbers within group A were too small to allow separate analysis between patients treated with ‘non-alkylating agents’ and those treated with ‘alkylating agents’.


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  		Table I. Patient characteristics in groups of patients lost in follow-up and participating patients.

 
Treatment
In group A, 10 patients received alkylating agents, i.e. CY, procarbazine and/or ifosfamide. The remaining three were treated with non-alkylating chemotherapy, such as methotrexate or idarubicine. In group B, all 12 patients received autologous or allogenic SCT after a standardized conditioning regimen including TBI (2 Gray (Gy) or 2x6 Gy) combined with high-dose alkylating chemotherapy (CY 60 mg/kg). Serum AMH concentrations were lower in patients as compared to controls (group A versus group C: P= 0.007, group B versus group C: P= 0.02) (Table II). Moreover, patients in group B were younger than controls (P< 0.05) and 20% of the patients were oligomenorrhoeic before treatment was started.


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  		Table II. Hormonal and sonographic characteristics before and after treatment in group A, B and C; patients treated with multi drug-chemotherapy, patients treated with stem cell transplant and controls, respectively.

 
After treatment
At follow-up, 24 patients were in complete remission. Three of them had relapsed, but were re-treated successfully. Only one patient was in partial remission. The median interval between the pre- and post-treatment visit was 5.0 years (range 1.2–11.1 years) (Table II).

In subgroup A, serum AMH, inhibin B levels and antral follicle count were significantly lower than in controls (P= 0.01; P= 0.02; P= 0.006, respectively). In addition, FSH levels were significantly increased (P= 0.03). Three (23%) women had continued OCPs immediately after finishing chemotherapy. In the group of patients with regular menstrual cycles at the start of therapy (n= 10), four (31%) had become oligomenorrhoeic and two (15%) amenorrhoeic. Three patients (23%) had regular cycles after treatment, of which one was oligomenorrhoeic prior to chemotherapy. The cycle pattern did not change in one patient (8%) who suffered from oligomenorrhoea prior to therapy.

In group B, serum AMH concentrations were significantly decreased, as were inhibin B levels, E2 levels and follicle count as compared to group C (P< 0.001), and FSH serum levels were increased (P< 0.001). In addition, all patients in group B were amenorrhoeic (Table II).

Prior to therapy, patients were younger than controls and had lower AMH levels than controls. Moreover, intervals between the first and last visit were different in the three subgroups. Therefore, the remaining fraction in AMH was calculated. In subgroup C, the remaining fraction of AMH reflected the normal decline in AMH serum levels during one year, independent from baseline AMH levels. Within one year, AMH serum levels decreased by 15% (median remaining fraction 85%; range 0–120%) in healthy normo-ovulatory women. The remaining fraction in subgroup A (median 73%; range 20–110%) was not different from that in controls (P= 0.42). In subgroup B, the remaining fraction (median 13%; range 0–50%) was significantly less than in controls (P< 0.001) (Table II) (Fig. 1).


Figure 1
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  		Figure 1: Decrease in serum AMH levels in relation to age in patients treated with multi-drug chemotherapy or stem cell transplant and controls; (Figure 1) Serum AMH levels in patients treated with multi-drug chemotherapy; (Figure 1) Serum AMH levels in patients treated with stem cell transplant; (Figure 1) Serum AMH levels in healthy controls; with upper line = 95th percentile, middle line = 50th percentile and lower line = 5th percentile

 
In group A, 3 patients conceived spontaneously within 5 years after finishing chemotherapy.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Regardless of their age or ovarian function prior to treatment, all patients treated with SCT developed premature ovarian failure (POF) and their serum AMH concentrations were undetectable. In accordance to data from literature, the conditioning regimen for SCT is a high risk factor for developing ovarian failure (Howell and Shalet, 1998Go). Moreover, TBI causes irreversible damage to the ovaries (Wallace et al., 1989Go). Hence, all women treated with SCT, especially those receiving TBI, are candidates for fertility preservation techniques, such as ovarian cryopreservation or vitrification of oocytes.

Serum AMH levels as well as antral follicle counts were significantly decreased in patients treated with chemotherapy alone. Although most of these patients had menstrual cycles and some of them conceived spontaneously after chemotherapy, sub-clinical ovarian damage had occurred. Hence, they might be at risk for POF as well and long-term follow-up of the reproductive function in these patients is necessary.

Three recent studies have described predictors for ovarian reserve in breast cancer survivors. In premenopausal patients treated with gonadotoxic chemotherapy, serum AMH and inhibin B levels were decreased after treatment, although the difference was statistically not significant. Antral follicle count was identified as the best predictor for ovarian function after chemotherapy (Lutchman et al., 2007Go). It may be hypothesized that directly after chemotherapy, the number of small growing follicles and eventually the number of antral follicles is decreased. Indeed, immediately after chemotherapy AMH levels fall rapidly, suggesting that most of the small growing follicles are lost during the first 3 months after therapy (Anderson et al., 2006Go). In most of their patients, AMH levels were undetectable and recovery of ovarian function did not occur, most likely because their ovarian reserve prior to therapy was reduced due to advanced age at start of chemotherapy. Hypothetically, in younger patients ovarian reserve is also diminished, but menstrual cycles will be restored, as observed in the current study. Until now, data are insufficient to determine the time-interval needed for recovery (Howell and Shalet, 1998Go). In another study, seemingly intact ovarian function was observed in women treated for breast cancer. These patients had regular menstrual cycles and normal antral follicle counts. However, most of these women had decreased inhibin B levels and 50% of them had increased FSH levels as well. Moreover, all these women had an entire ovary removed for cryopreservation prior to treatment. Hence, these women had an additional risk factor for compromised ovarian function after cancer therapy (Schmidt et al., 2005Go).

Prior to therapy, AMH levels in patients were lower than in controls, even though the latter group was older. This indicates that ovarian reserve in patients was already compromised before any therapy was initiated. Remarkably, all patients who developed POF after gonadotoxic chemotherapy had pretreatment AMH levels lower than the 10th percentile of AMH levels in age-matched controls. However, not all patients with pretreatment AMH below this threshold point developed POF. Hence, in our study sample, AMH levels prior to treatment were not predictive for ovarian reserve after treatment.

The remaining fraction of AMH in patients treated with chemotherapy alone, reflecting the decrease in AMH levels per year, was not significantly different from that of controls. This suggests that ovarian damage following gonadotoxic therapy is due to a diminished primordial follicle pool rather than to an increased rate of follicle loss, as described earlier (Anderson et al., 2006Go).

In conclusion, the present data show that patients receiving TBI developed POF. Hence, to these women fertility preservation, either through unilateral ovariectomy and subsequent cryopreservation or vitrification of collected oocytes, should be offered. In patients treated with multi-drug chemotherapy, the ovarian reserve is compromised as well. Although to a lesser extent, these patients are also at risk for premature menopause.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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Submitted on July 26, 2007; resubmitted on November 6, 2007; accepted on November 14, 2007.


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