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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2374
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 10 3869-3874
Copyright © 2007 by The Endocrine Society

Anti-Müllerian Hormone Is a Sensitive Serum Marker for Gonadal Function in Women Treated for Hodgkin’s Lymphoma during Childhood

Robert D. van Beek, Marry M. van den Heuvel-Eibrink, Joop S. E. Laven, Frank H. de Jong, Axel P. N. Themmen, Friederike G. Hakvoort-Cammel, Cor van den Bos, Henk van den Berg, Rob Pieters and Sabine M. P. F. de Muinck Keizer-Schrama

Department of Pediatric Hematology/Oncology (R.D.v.B., M.M.v.d.H.-E., F.G.H.-C., R.P.), and Department of Pediatric Endocrinology (R.D.v.B., S.M.P.F.d.M.K.-S.), and Erasmus MC–Sophia Children’s Hospital Rotterdam, and Department of Gynecology and Obstetrics (J.S.E.L.), Division of Reproductive Medicine, and Department of Internal Medicine (F.H.d.J., A.P.N.T.), Erasmus MC Rotterdam, 3000 CB Rotterdam, The Netherlands; and Department of Pediatric Oncology (C.v.d.B., H.v.d.B.), Emma Children’s Hospital-Academic Medical Center Amsterdam, 1100 DE Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Sabine M. P. F. de Muinck Keizer-Schrama, Erasmus MC/Sophia Children’s Hospital, Room Sp3435, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands. E-mail: s.demuinckkeizer-schrama{at}erasmusmc.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Purpose: The aim of this study was to evaluate the long-term effects of combination chemotherapy treatment for girls with Hodgkin’s lymphoma (HL) on gonadal function using anti-Müllerian hormone (AMH) and inhibin B as ovarian reserve parameters.

Patients and Methods: LH, FSH, inhibin B, and AMH were measured in 32 women treated from 1974 to 1998 for pediatric HL with chemotherapy, with the intention to avoid radiotherapy. All patients [median age 25.0 yr (range 19.2–40.4 yr)] were in complete remission with a median follow-up time of 14.0 yr (range 5.7–24.5 yr) after therapy. All patients were treated with combination chemotherapy doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) or EBVD with or without mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). Because of incomplete remission or relapse, involved field radiotherapy was needed in seven of 32 women. Results were compared with a healthy control group.

Results: Patients treated with six or more cycles of MOPP combination chemotherapy had significantly higher levels of FSH and lower serum levels of inhibin B and AMH, compared with healthy women [FSH, 17.0 vs. 6.0 U/liter (P < 0.05); inhibin B, 23.0 vs. 112.5 ng/liter (P < 0.01); AMH, 0.39 vs. 2.10 µg/liter (P < 0.01)]. AMH was also significantly lower, compared with women treated without MOPP (median 0.39 vs. 1.40 µg/liter; P = 0.01).

Conclusions: Women treated during childhood for HL with MOPP seem to have a distinctly lower ovarian reserve as measured by lower AMH values at early adulthood, compared with healthy women. Moreover, AMH seems to be the only predictor that is sufficiently sensitive to detect this decrease in ovarian reserve.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE MAJORITY OF treatment protocols for Hodgkin’s lymphoma (HL) consist of a combination of chemotherapy and radiotherapy. Using this strategy, childhood HL currently has an event-free survival of about 90–95% and an overall survival of up to 96% (1, 2, 3, 4). Because of the improved survival rates, long-term side effects are an important issue (5). Most of the studies report on late effects in adult HL patients, and little is known on the endocrine long-term effects in children treated for HL. In adults, an important long-term effect of both radiotherapy and chemotherapy is decreased gonadal function, especially after chemotherapy protocols containing high cumulative doses of potentially gonadotoxic agents such as mechlorethamine and procarbazine (e.g. MOPP or COPP) (6, 7, 8, 9).

Usually gonadal function is measured in follow-up studies of long-term survivors of childhood cancer by analysis of LH and FSH. However, neither LH nor FSH correctly reflects the ovarian reserve (10). In recent years, two new markers for ovarian function became available. Inhibin B, which is solely produced by granulosa cells of small antral follicles, is decreased in women with known fertility problems (e.g. premature ovarian failure) and undetectable in postmenopausal women (11, 12, 13). Inhibin B is one of the first endocrine markers to change in perimenopausal women, even before changes in FSH levels can be detected (14). The second new marker is anti-Müllerian hormone (AMH). This hormone is produced by granulosa cells of early developing (pre-)antral follicles of the ovary, and levels decrease when the number of follicles decreases with age (15). A recent study showed a strong correlation between age at menopause and AMH levels randomly measured during the reproductive life span (ages 20–36 yr) in a group of healthy women (16).

The aim of this study was to evaluate the gonadal long-term effects in women after treatment for childhood HL with combination chemotherapy with the intention to avoid radiotherapy using inhibin B and AMH as predictors of ovarian reserve.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and treatment protocols

From a total group of 151 pediatric HL patients, 51 female long-term survivors treated from 1974 to1998 in Erasmus MC-Sophia Children’s Hospital and Emma Children’s Hospital-Academic Medical Center were identified. From this group 11 patients refused participation (21.5%) and eight patients were lost to follow-up (15.7%). There were no significant differences in age and disease characteristics between the included 32 female survivors and those not included (Table 1Go).


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  		TABLE 1. Comparison between included and excluded female patients

 
Two of the 32 included women were pregnant at the time of study. Because pregnancy is known to affect serum concentrations of the hormones involved in the pituitary-ovarian axis, no laboratory parameters were included of these women. All patients were in complete remission with a median duration of 14.0 yr (range 5.7–24.5 yr). The median age at follow-up was 25.0 yr (range 19.2–40.4 yr). All patients were treated with combination chemotherapy ABVD or EBVD with or without MOPP as previously described (2, 3). ABVD included 25 mg/m2 Adriamycin (epirubicin 30 mg/m2 in EBVD), 10 mg/m2 bleomycin, 6 mg/m2 vinblastine, and 250 mg/m2 dacarbazine on d 1 and 8. MOPP included 6 mg/m2 mechlorethamine and 2 mg/m2 vincristine (maximum 2.5 mg/dose) on d 1 and 8, 40 mg/m2·d prednisone and 100 mg/m2·d procarbazine on d 1–14 (1, 2). The primary aim of this protocol was to maintain good survival rates but to avoid radiotherapy. However, seven of 32 patients needed additional involved field radiotherapy because of incomplete remission with chemotherapy only (four treated with MOPP and one treated without MOPP), or relapse (two treated with MOPP). None of the patients received irradiation below the diaphragm. Scatter irradiation to the gonads is approximately 0.5% of the total dose. Patients were categorized into three treatment groups according to the number of MOPP cycles: no MOPP (n = 7), three to four MOPP (n = 14), and six or more MOPP cycles (n = 9). Only one patient was treated with four MOPP courses and none of the patients were treated with one, two, or five MOPP cycles. The medical ethical committee approved this study, and informed consent was obtained from all patients according to the Helsinki agreement.

Levels of FSH, LH, estradiol, inhibin B, and AMH were compared with normal values from a group of 41 randomly selected healthy normoovulatory women (aged 20–35 yr; median age 29 yr) not using oral contraceptives (OCPs) or any other hormonal treatment at least 3 months before start of the study, as described previously (15). Samples were drawn on the third day of the menstrual cycle in all control subjects.

Laboratory measurements

Blood samples were processed within 2 h after withdrawal and stored at –20 C until assay. All blood samples were drawn on the third to fifth day of the menstrual cycle or when women used OCP on the last day of the pill-free interval (17). Endocrine screening included serum assays for FSH, LH (both fluorescence-based immunometric assays on the Immulite 2000; Diagnostic Products Corp., Los Angeles, CA), estradiol (coated tube RIA; Diagnostic Products), inhibin B (enzyme-immunometric assay; Serotec, Oxford, UK), and AMH (Diagnostic Systems Laboratories, Webster, TX). Intra- and interassay coefficients of variation were less than 5 and 15% for LH, less than 3 and 8% for FSH, less than 5 and 7% for estradiol, less than 9 and 15% for inhibin B, and less than 5 and 8% for AMH, respectively (15).

Questionnaires

All patients completed a questionnaire regarding previous pregnancies, menarche, menstrual cycle, and the use of OCPs. In addition, information was obtained on smoking, alcohol consumption, exposure to toxic agents or radiation, and use of medication.

Statistics

Statistical analysis was performed using SPSS 12.0.1 (SPSS Inc., Chicago, IL). Kruskal-Wallis tests were used to check for trends in the treatment groups and healthy controls. Differences between the separate treatment groups were tested using Mann-Whitney U tests. Differences between the groups in the data of the questionnaires were also tested using a Kruskal-Wallis test. P < 0.05 (two tailed) was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical characteristics

Patient characteristics at time of study are shown in Table 2Go. Median values for body mass index were 23.6 kg/m2 in MOPP– patients and 24.0 kg/m2 in MOPP+ patients. Eighteen women used OCPs and one woman used hormone replacement therapy. Three women treated with MOPP, currently using OCPs reported previous irregular menses. None of the 12 women without OCPs had irregular menses. A total of 17 pregnancies were reported in 11 women, resulting in 10 healthy children; one pregnancy was ended electively, four pregnancies (three of which in one woman) ended in spontaneous abortion (23.5%), and two women were pregnant at the time of the study. Two pregnancies (both MOPP+; 10 and six cycles, respectively) were achieved using assisted reproductive techniques (one intrauterine insemination, one in vitro fertilization with egg donation), both resulting in the delivery of a healthy live-born child. One woman used hormone replacement therapy because of overt premature ovarian failure. There were no significant differences in the use of alcohol, smoking, or exposure to toxic agents between MOPP+ patients and MOPP– patients.


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  		TABLE 2. Patient characteristics of included women

 
Hormone levels

Figure 1Go shows the hormone levels for the different treatment groups and the healthy controls. No differences in LH levels between any of the treatment groups and healthy controls were found. FSH levels were significantly higher in patients treated with six or more MOPP cycles, compared with healthy controls (P < 0.05) and compared with those treated without MOPP (P < 0.05). Trend analysis for higher FSH with increasing number of MOPP courses was not significant. Inhibin B levels were significantly lower in all treatment groups, compared with healthy controls (P < 0.05 for 0 MOPP; P < 0.01 for three to four MOPP; P < 0.01 for six or more MOPP). Inhibin B levels decreased significantly with increasing number of MOPP cycles (P < 0.001). Estradiol levels were significantly lower in patients treated without MOPP (P < 0.01), compared with healthy controls. AMH levels were significantly lower in both patients treated with three to four MOPP cycles (P < 0.05) and patients treated with six or more MOPP cycles (P < 0.01), compared with healthy controls and compared with patients treated without MOPP (P < 0.05 for three to four MOPP as well as six or more MOPP; trend analysis, P < 0.001).


Figure 1
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  		FIG. 1. Serum levels of LH, FSH, inhibin B, AMH, and estradiol in patients with various numbers of MOPP cycles and healthy controls. Lines indicate medians. *, P < 0.05; **, P < 0.01, compared with healthy controls; $, P < 0.05, compared with no MOPP.

 
All women with increased FSH levels had decreased AMH levels, three women with normal FSH levels had decreased AMH levels adjusted for age. No significant correlations were found between FSH and inhibin B (P = 0.42). However, AMH and FSH levels (rs = –0.52; P < 0.01) and AMH and inhibin B (rs = 0.43; P < 0.05) were significantly correlated. Five women with decreased AMH levels had inhibin B levels within normal limits.

There were no significant differences in AMH or inhibin B levels between patients who needed additional radiotherapy, compared with patients treated without additional radiotherapy (P = 0.08 and P = 0.31, respectively). LH and FSH levels were significantly higher in patients who needed additional radiotherapy, compared with patients who did not (LH 21.1 vs. 12.3 U/liter, P < 0.05 and FSH 20.3 vs. 12.6 U/liter, P < 0.05).

Women using OCPs had significantly lower LH levels, compared with women not on OCPs (2.2 vs. 5.9 U/liter, P < 0.05), although both median values were within normal range. There were no significant differences in FSH, inhibin B, and AMH between women who used OCP and women who did not use OCPs. The woman on hormone replacement therapy had lower inhibin B and AMH in concordance with the reported ovarian failure in the questionnaire.

Hormone levels and age

Hormone levels were not influenced by age at treatment (data not shown) and did not differ between women treated before puberty and women treated during puberty (Table 3Go). Figure 2Go shows the AMH and FSH serum levels according to age at follow-up. All women treated without MOPP had normal AMH levels for age, whereas 10 of 17 MOPP+ women had AMH levels below the 95% confidence interval for healthy controls. FSH serum levels were increased in nine of 21 MOPP+ women; in all but one MOPP– patient, levels were below the upper 95% confidence interval and in one on the upper 95% confidence interval. The use of OCPs did not differ between women with normal vs. decreased levels of AMH or increased levels of FSH.


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  		TABLE 3. Hormone levels and puberty at time of diagnosis

 

Figure 2
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  		FIG. 2. AMH levels and FSH levels in Hodgkin lymphoma patients treated with or without MOPP vs. normal controls in relation to age. Solid lines, Mean healthy controls; dashed lines, 95% confidence interval of healthy controls (only lower limit in AMH graph); {circ}, healthy controls; {blacksquare}, MOPP+; {square}, MOPP–.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Because HL in childhood has become a curable disease, long-term effects of the treatment become increasingly important. We investigated gonadal function in women treated for HL during childhood and compared the effects of treatment with (MOPP+) and without (MOPP–) alkylating agents. This study provides the first systematic, very long-term outcome study (12 yr of follow-up) for gonadal function in women treated for childhood HL without initial radiotherapy, using up-to-date fertility markers like AMH and inhibin B. So far, only two studies reported on long-term effects after childhood HL treatment with chemotherapy; however, with shorter follow-up and using only FSH and LH as markers for ovarian function (18, 19).

In this study, FSH serum levels were increased and inhibin B concentrations were generally lower in HL survivors. However, AMH levels were decreased, even in those patients that exhibited normal FSH values, indicating that AMH is an earlier and more sensitive marker to detect gonadal damage. This suggests that AMH can be useful for counseling young women who survived childhood cancer regarding their fertility status and family planning. Subsequently, further loss of ovarian reserve in these women could be monitored on the basis of AMH serum levels.

In the current study, AMH levels were significantly lower in MOPP+ women, compared with MOPP– women. One of them was treated for premature ovarian failure with hormone replacement therapy, whereas three women reported irregular menses after MOPP. Interestingly, already at a very young age (20–25 yr), women treated with MOPP had AMH levels comparable with those found in perimenopausal women, indicating loss of ovarian reserve and increased risk of premature ovarian failure. This suggests that premature ovarian failure is a disguised long-term follow-up problem, for which AMH is the only reliable marker, not only in women with a regular menstrual cycle but also in those using OCPs (20, 21). AMH is produced by not only small antral follicles but also all smaller follicles from primary follicles onward (22), which may not be seen on an ultrasound of the ovaries. Therefore, AMH constitutes a more sensitive marker for ovarian reserve than the determination of the antral follicle count by ultrasound, which is more time consuming and not always possible in young adolescents (23). AMH is a good predictor of the number of oocytes and a marker for ovarian aging (15, 24, 25). In healthy controls AMH decreases with age as the number of follicles in the ovary decreases (26), and AMH levels can be used as a predictor for menopause (16). Another advantage of using AMH as a predictive marker for ovarian failure is that AMH is not influenced by confounding factors, such as OCP use, day of menstrual cycle, and pregnancy (20). Therefore, it is a promising marker for ovarian reserve in all women, although it is not yet fully established in clinical care and more research is needed.

The use of MOPP has major consequences on ovarian reserve. AMH levels in the MOPP+ group were lower, compared with the MOPP– group, but also AMH levels decreased significantly with an increasing number of MOPP courses. This suggests that the used treatment regimen and the number of MOPP courses are the main factors that affect ovarian reserve. To our knowledge no studies exist on the effect of the disease itself on gonadal function in female patients. Because no data are available on pretreatment values of the hormonal measurements, no conclusions on that matter can be drawn.

There are few data on inhibin B levels in women after treatment for childhood cancer. Bath et al. (27) reported no differences in inhibin B levels between long-term survivors and healthy controls; however, the majority of patients were treated with chemotherapy without alkylating agents, and only two women treated for HL were included. Larsen et al. (28) reported lower inhibin B levels in women (among which seven patients treated for childhood HL) treated with alkylating agents and radiotherapy. The present study is the first study to describe inhibin B levels as a marker for ovarian reserve in women in which the majority (25 of 32) was treated for HL during childhood with chemotherapy only. Although inhibin B serum levels were slightly lower in MOPP+ women, this difference did not reach significance. Apparently, inhibin B and FSH constitute late markers of depletion of the primordial follicle pool, whereas AMH levels are directly proportional with the number of primordial follicles, i.e. the ovarian reserve. Moreover, AMH is superior to inhibin B in detecting depletion of the ovarian reserve as demonstrated by the patients with low AMH levels and normal inhibin B levels in our study. Furthermore, AMH levels are at least an order of magnitude larger than those of inhibin B, making it easier to estimate the former parameter, which is reflected in the lower intra- and interassay coefficients of variation for AMH. Finally, assay costs for AMH and inhibin B are comparable.

In the current study, LH levels did not differ between the treatment groups and healthy controls. However, FSH levels in patients treated with six or more MOPP cycles were significantly higher, compared with those treated without MOPP or healthy controls. The lower estradiol levels in both MOPP– women and those with three to four MOPP cycles, compared with the healthy control group, might be explained by the use of OCPs in our study group in contrast to the control group. It is known that LH remains normal in a large majority of patients after chemotherapy with alkylating agents (18, 29, 30), whereas FSH is increased in 15–50% of the women (18, 30). This so-called monotropic rise in FSH without an increase in LH is characteristic for premature ovarian failure as well as women with an abnormal menstrual cycle (23). FSH itself is not sensitive enough to detect early loss of ovarian reserve, whereas AMH, as mentioned before, has been shown to be a more reliable predictor in this respect (22).

The abortion rate of 23.5% appears to be very high in our study, compared with other studies on long-term effects of treatment (31). However, of the four pregnancies that ended in a spontaneous miscarriage, three were reported by the same patient (MOPP+). Most women who reported one or more pregnancies had normal AMH levels for age at the time of study. However, AMH levels at time of pregnancies were not available, and because AMH rapidly decreases with age, women with low AMH levels at time of study might very well have had normal AMH levels at time of pregnancy.

The number of pregnancies is difficult to compare with other studies because many different confounders are involved such as fertility of the partner and time to pregnancy. The percentage of women becoming pregnant after treatment for HL in previous studies varies from less then 10% (18) to almost 30% (32). It might be that a considerable group of women in the current study was not yet thinking of family planning. The median age in our study group is 25 yr, whereas the mean age at which women in The Netherlands have their first child is 29.3 yr (33). Moreover, this study was not designed or powered to assess fertility or pregnancy outcome, and the pregnancy data therefore cannot be extrapolated. Unfortunately, data on time to pregnancy were not available in our study.

In conclusion, the present study shows that women treated with chemotherapy during childhood for HL do show a distinct decrease in ovarian reserve. AMH constitutes the most sensitive predictor, superior over FSH, and inhibin B for ovarian reserve in these women. Hence, AMH serum levels can be used during follow-up of these childhood cancer survivors to predict incipient ovarian failure. Consequently, AMH may be a valuable predictive marker in patients for fertility counseling and future family planning.


   Acknowledgments
 
The authors thank Manita van Baalen and Heleen van der Pal from the follow-up outpatient clinics in Rotterdam and Amsterdam for their assistance in collecting patient data.


   Footnotes
 
Disclosure Statement: R.D.v.B., M.M.v.d.H.-E., J.S.E.L., F.H.d.J., A.P.N.T., F.G.H.-C., C.v.d.B., H.v.d.B., R.P., and S.M.P.F.d.M.K.-S. have nothing to declare.

First Published Online August 28, 2007

Abbreviations: ABVD, Adriamycin, bleomycin, vinblastine, and dacarbazine; AMH, anti-Müllerian hormone; COPP, cyclophosphamide, vincristine, procarbazine, and prednisone; EBVD, epirubicin, bleomycin, vinblastine, and dacarbazine; HL, Hodgkin’s lymphoma; MOPP, mechlorethamine, vincristine, procarbazine, and prednisone; OCP, oral contraceptive.

Received October 30, 2006.

Accepted July 20, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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