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The Fertility Clinic (E.C.L., A.N.A.), the Department of Growth and Reproduction (J.M.), Pediatric Clinic II (K.S., C.R.), Late Effects Clinic (C.R.), and Department of Pediatrics (J.M.), The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, DK–2100 Copenhagen, Denmark
Address all correspondence and requests for reprints to: Dr. Elisabeth C. Larsen, The Fertility Clinic, Section 4071, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: elisabeth.larsen{at}dadlnet.dk.
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Abstract |
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Ovarian function was evaluated in 100 childhood cancer survivors and 21 controls of similar age. Menstrual cycle pattern was recorded, and strictly timed ovarian sonography and hormonal assessment were performed.
The median age of the survivors was 5.4 yr (range, 0.1–15.3) at the time of diagnosis and 25.7 yr (18.5–44.4) at study entry. Seventeen survivors with premature ovarian failure had follicle-depleted or nondetectable ovaries, elevated FSH and LH, and immeasurable inhibin B. Thirteen survivors used oral contraception. Survivors with spontaneous menstrual cycles (n = 70) had smaller ovarian volume per ovary than controls (median, 4.8 vs. 6.8 cm3; P < 0.001) and a lower number of antral follicles per ovary (median, 7.5 vs. 11; P < 0.001). Further, they had lower inhibin B levels than controls (median, 94 vs. 111 pg/ml; P = 0.03) and higher estradiol levels (median, 0.12 vs. 0.08 pM; P = 0.04). Multiple linear regression analysis was performed to predict the total antral follicle number per ovary, and it showed a reduced number with ovarian irradiation (ß = -0.40, P < 0.001), alkylating chemotherapy (ß = -0.25, P = 0.01), older age at diagnosis (ß = -0.25, P = 0.01), and longer time period off treatment (ß = -0.19, P = 0.044).
One in every six female survivors may develop premature ovarian failure. In survivors with spontaneous menstrual cycles, the results indicate a diminished ovarian reserve. Consequently, cessation of fertility may occur much earlier than anticipated. Adult survivors with spontaneous cycles should be informed hereof to plan childbearing.
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Introduction |
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The nonrenewable pool of ovarian primordial follicles declines, by atresia, from 2 million at birth to 500,000 at menarche. When the total number reaches 25,000 at a mean age of 37–38 yr, the loss accelerates, and spontaneous and assisted conceptions get increasingly difficult (7). At a mean age of 50–51 yr, the primordial follicle pool falls below a key threshold number, and natural menopause occurs. Any radiation- or chemotherapy-induced insult that hastens the natural decline in follicle numbers may lead to an early menopause.
The ovarian follicular depletion in childhood cancer survivors has generally been evaluated by indirect measurements such as presence or absence of a menstrual cycle, endocrine profiles, and the risk of developing ovarian failure in relation to different treatment-modalities (8, 9, 10, 11). However, transvaginal ovarian sonography in the early follicular phase of a menstrual cycle (cycle d 2–5) is an important tool when predicting ovarian function both in women undergoing assisted reproductive techniques and in women with proven natural fertility. It has been shown that both the ovarian volume and the antral follicle number reliably reflect the size of the remaining primordial follicle pool, i.e. the ovarian reserve (12, 13, 14, 15, 16, 17).
Our aim was to assess ovarian function in a large cohort of childhood cancer survivors to provide a more comprehensive knowledge of the degree of ovarian damage. Therefore, we combined clinical data with strictly timed ovarian sonography and hormone level analysis.
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Patients and Methods |
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From the Childhood Cancer Registry, a cohort of female survivors, diagnosed and treated, in the eastern part of Denmark, for a noncentral nervous system childhood cancer was identified.
Included were survivors who were: 1) diagnosed in the period from January 1970 through December 1996; 2) less than or 15 yr old (median, 5.4 yr; range, 0.1–15.3) at the time of diagnosis; 3) treated with radiotherapy and/or chemotherapy; 4) off treatment for at least 1 yr at study inclusion (median, 16.8 yr; range, 3.8 to 28.8); 5) in complete remission (first n = 86, second n = 12, third remission n = 2); and 6) at least 18.0 yr old (median, 25.7 yr; range, 18.5 to 44.4) at study inclusion.
A total of 165 female survivors fulfilled the criteria. Thirty-one survivors were lost to follow-up or had moved to another country, five had had a hysterectomy, and four had mental disorders and were institutionalized. Twenty-five of the remaining 125 eligible survivors declined or did not reply to the invitation. Thus, 100 survivors participated in the study (participation rate, 80%).
The childhood malignancies included acute lymphoblastic leukemia (n = 47), acute myeloid leukemia (n = 2), chronic myeloid leukemia (n = 1), non-Hodgkin lymphoma (n = 6), Hodgkin’s disease (n = 7), Wilms’ tumor (n = 18), neuroblastoma (n = 9), Ewing’s sarcoma (n = 2), soft-tissue sarcoma (n = 5), osteosarcoma (n = 1), and teratoma (n = 2).
The 25 nonresponders were significantly older at diagnosis than the participants (median, 10.4 vs. 5.4 yr; P = 0.042). However, they did not differ significantly with regard to age at follow-up (median, 26.7 vs. 25.7 yr), time off treatment (median, 18.0 vs.16.8 yr), distribution of diagnoses (76 vs. 63% hematological malignancies and 24 vs. 37% solid tumors), and treatment regimens.
As part of the research program, 21 controls were recruited by means of advertisement at the Danish School of Art and Design, the Copenhagen School for Midwifes, and the Copenhagen University. They had a median age of 26.4 yr (range, 21.5 to 34.7), which was not significantly different from the 100 survivors (25.7 vs. 26.4 yr, P = 0.4). They were selected on the basis of no use of oral contraceptives (OC) in the preceding 3 months and regular menstrual cycles (cycle lengths, 21–35 d). The controls received monetary compensation for study participation.
Treatment
For all survivors, cumulative doses of applied chemotherapy and radiotherapy were calculated. Further, it was noted, from x-rays, whether the ovaries were within the irradiation field.
Surgery.
Thirty-seven survivors with solid tumors had surgery performed that in no case involved the ovaries. Two survivors had a transposition of the ovaries performed to protect them from direct ovarian irradiation in an inverted Y field.
Chemotherapy.
All 100 survivors received chemotherapy. Alkylating agents included cyclophosphamide, ifosfamide, nitrosoureas, busulfan, melphalan, mustagene, chlorambucil, dacarbazine, procarbazine, and cisplatinum. Except for cyclophosphamide, which was given to 44 survivors, the other alkylating agents were given to less than five survivors each. Other DNA-damaging agents were doxorubicin, dactinomycin, daunorubicin, bleomycin, adriablastine, VM-26, and vepeside. Except for doxorubicin, dactinomycin, and daunorubicin, which were given to 41, 27, and eight survivors, respectively, the other DNA-damaging agents were given to less than five survivors each. Other cytotoxic agents included asparaginase (given to 44 survivors), methotrexate (given to 53), steroids (given to 29), 6-mercaptopurine (given to 39), thioguanine (given to nine), vincristine (given to 85), vinblastine (given to four), and cytarabine (given to 24).
Radiotherapy.
Fifty-six patients received radiotherapy. Of these, 49 patients received radiotherapy to one field, six patients to two fields, and one patient to three fields. Sixteen received cranial irradiation (median total dose, 24 Gy; range, 16–30), and 12 received irradiation to other fields above the diaphragm (median total dose, 37 Gy; range, 24–54). Ten patients received total body irradiation (median total dose, 11.3 Gy; range, 8.5–12.5), and thus, direct irradiation to the ovaries, which was also the case in six patients where whole abdominal or pelvic irradiation was given (median total dose, 30.6 Gy; range, 25.9–54.1). Twenty patients received radiotherapy by other fields below the diaphragm (median total dose, 30.1 Gy; range, 12–40.5), and the ovaries could potentially have received indirect irradiation/scatter.
Bone marrow transplantation.
Twelve survivors were cured with bone marrow transplantation. The conditioning regimens were, in 10 survivors, total body irradiation as described above and cyclophosphamide (median total dose, 3.9 g/m2; range, 3.2–4.3), whereas two patients received alkylating agents only (4.5 g/m2 cyclophosphamide and 632 mg/m2 busulfan or 100 mg/m2 melphalan and 548 mg/m2 busulfan).
Treatment groups.
The 100 female survivors were divided into three groups according to presumed impact on ovarian function (Table 1
). The seven patients who had received irradiation to more than one field were allocated to the group where the radiotherapy had induced the highest degree of ovarian damage.
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Group 2 included 55 survivors who were treated with either: chemotherapy including alkylating agents (n = 12), chemotherapy including alkylating agents and radiotherapy above the diaphragm (n = 18), chemotherapy including alkylating agents and radiotherapy below the diaphragm (n = 13), or radiotherapy below the diaphragm and nonalkylating cytotoxic agents (n = 12).
Group 3 included 10 survivors treated with total body irradiation and cyclophosphamide before allogeneic bone marrow transplantation.
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Methods |
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Controls and survivors with spontaneous menstrual cycles were examined in the early follicular phase of a menstrual cycle, i.e. cycle d 2–5. Survivors using OC or estrogen-progestogen hormonal replacement therapy (HRT) were examined during withdrawal bleeding on d 2–5. The OC contained 20–40 µg ethinyl estradiol, and the postmenopausal hormone therapy contained 2 mg estradiol from cycle d 5–26 and 1 mg from cycle d 27–4. For survivors and controls, age at menarche and menstrual cycle pattern were registered. Further, height, weight, and pubertal maturation according to Tanner criteria were measured. In all survivors, the investigator (E. C. Larsen) recorded diagnosis and treatment.
Ovarian sonography.
Ovarian sizes were measured by transvaginal sonography with a 6.5-MHz probe using the Panther type 2002 ADI (B-K Medical, Gentofte, Denmark). Two survivors, who were uncomfortable with transvaginal sonography, had a transabdominal sonography. The length and height of the ovaries were measured in the sagital section and the width in the transverse section after a 90° rotation of the transducer. Ovarian volumes were calculated as: d1 x d2 x d3 x 
/6, where d1, d2, and d3 are the three maximal longitudinal, anteroposterior, and transverse diameters. The ovarian volume was registered as the mean volume of two ovaries. If only one ovary was identified, the volume of this ovary was registered. The number of small antral follicles no more than 5 mm and the number of larger antral follicles more than 5 mm and no more than 10 mm were counted, while the transducer was moved from the outer to the inner margin of the ovary. The same sonographer (E. C. Larsen) performed and videotaped all ultrasound examinations. If one or both ovaries could not be identified, an additional experienced examiner scanned the patient as well.
Hormone analysis.
Venous blood samples were collected between 0800 h and 1000 h and analyzed for basal levels of FSH, LH, estradiol, inhibin A, inhibin B, testosterone, TSH, total T4, SHBG, and prolactin (PRL). All hormone concentrations were measured with commercially available kits: FSH, LH, PRL, and total T4 with a kit from Abbott Laboratories (Abbott Park, IL); TSH and SHBG with a kit from Delfia (Wallac, Turku, Finland); estradiol with a kit from Pantex (Santa Monica, CA); and testosterone with a kit from Diagnostic Products Corporation (Los Angeles, CA).
AxSYM FSH, LH, and PRL are based on microparticle enzyme immunoassay technology. The upper 95% limit of the sensitivity determination for FSH-assay, LH-assay, and PRL-assay are 0.37, 0.5, and 14.4 mIU/liter, respectively. AxSYM total T4 is a fluorescence polarization immunoassay with a sensitivity of 1.05 µg T4/dl.
AutoDELFIA is a time-resolved fluoroimmunoassay. The intra- and interassay coefficients of variation (CVs) are less than 5% for TSH and less than 8% for SHBG. PANTEX (E2)125I kit measures estradiol in serum using the principles of RIA. The sensitivity is 10 pg/ml, the intraassay CV is 4.3%, and the interassay CV is 5.1%. COAT•A•COUNT total testosterone is a solid-phase 125I RIA with a sensitivity of 0.14 nM.
Serum inhibin A and inhibin B were measured in duplicate in double-antibody enzyme immunometric assays (Oxford, Bio-Innovation Ltd., Oxford, Oxon, UK) using monoclonal antibodies raised against the inhibin subunits (ßA-chains and ßB-chains). The detection limits were 7 and 20 pg/ml for inhibin A and inhibin B, respectively. Intra- and interassay CVs were less than 15% for inhibin A and less than 16% for inhibin B.
Statistics.
Results are presented as medians and ranges. Kruskal-Wallis rank test was performed to analyze the variance of three or more groups. Comparisons between two independent groups were done using the Mann-Whitney U test. If variables were normally distributed and tests for equality of variance were accepted, data from three groups were compared by one-way ANOVA and multiple comparisons with a modified t test (Bonferoni correction). Correlations between variables were tested with Spearman’s correlation analysis (rs = correlation coefficient). Stepwise, backward, multiple, linear regression analysis was done to clarify the most important factors for the variations in total antral follicle count. The independent variables were: age at diagnosis, time period off treatment, alkylating chemotherapy (given = 1, not given = 0), direct irradiation to the ovary (given = 1, not given = 0), and bone-marrow transplantation (given = 1, not given = 0). The validity of the model was checked using standard tests, which included assessing the distribution of residuals, testing for normality, and checking the linearity assumptions. In this analysis, the total antral follicle number per ovary was set to zero if both ovaries could not be identified by sonography and the participant used HRT because of treatment-induced ovarian failure. P < 0.05 was considered statistically significant, and all analyses were performed using SPSS (Chicago, IL) software (Statistical Package for Social Sciences) for Windows, version 10.0.
Ethics.
All participants gave their written informed consent. The study is in accordance with the Helsinki II declaration and approved by the regional ethical committee of Copenhagen, Denmark [approval (KF) 01-007/99].
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Results |
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Table 2 shows that 70 survivors reported spontaneous menstrual cycles, 13 used OC, and 17 used HRT because of treatment-induced ovarian failure. Ninety-two survivors had progressed through puberty spontaneously and had experienced menarche within the normal age range. Age at study inclusion was significantly higher in survivors using HRT, compared with survivors with spontaneous menstrual cycles (P = 0.03) and survivors using OC (P = 0.003).
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shows results from the ovarian sonography in survivors and in controls. In pair-wise analysis, the control group had significantly larger ovaries, a significantly higher number of small antral follicles, and a significantly higher number of total antral follicles, compared with survivors with spontaneous cycles, OC users, and HRT users (P < 0.001 in all comparisons). Further, survivors using HRT had significantly smaller ovaries (P < 0.001) and a significantly lower number of antral follicles (P < 0.001), compared with survivors with spontaneous cycles and OC users. Survivors with spontaneous cycles had significantly larger ovaries than OC users (P = 0.002); but with regard to follicle numbers, no significant differences were found.
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summarizes results from the hormone level analyses in survivors and in controls. Significant differences (P < 0.001) were found between the groups for all hormone levels except PRL. In pair-wise analyses, the HRT-group had significantly higher FSH, LH, and estradiol levels and significantly lower inhibin B and testosterone levels, compared with survivors with spontaneous cycles, OC users, and controls (P < 0.05 in all comparisons). The control group had significantly higher inhibin B levels (P = 0.03) and a significantly lower estradiol level (P = 0.04), compared with survivors with spontaneous cycles. With regard to FSH, LH, testosterone, inhibin A, and SHBG, no significant differences were found between these two groups. As expected, the OC group had a significantly higher SHBG level, compared with survivors with spontaneous cycles, HRT users, and controls (P < 0.001), as well as significantly lower inhibin B, FSH, estradiol, and LH levels, compared with survivors with spontaneous cycles and the control group (P < 0.05 in all comparisons). Inhibin A was significantly higher in survivors with spontaneous cycles, compared with survivors using OC (P = 0.003) and HRT (P = 0.001). All participants had normal values of TSH and total T4, including survivors using T4 replacement therapy because of thyroid insufficiency after total body irradiation or mantle irradiation (data not shown).
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Treatment characteristics
Survivors who used HRT at study entry were, in seven cases, cured with total body irradiation and alkylating chemotherapy before bone-marrow transplantation (group 3, Table 1
). Another seven were cured with radiotherapy below the diaphragm, with or without alkylating agents, and three were cured with alkylating agents and radiotherapy above the diaphragm (group 2). Survivors who used OC at study entry were, in seven cases, cured with regimens from group 1; and in six cases, with regimens from group 2. Survivors with spontaneous menstrual cycles were, in 28 cases, cured with regimens from group 1; in 39 cases, with regimens from group 2; and in three cases, with regimens from group 3.
Figures 1 and 2 show the results from the ovarian sonography in survivors with spontaneous menstrual cycles in relation to treatment-group and in the controls. A significant difference was found between the groups, regarding ovarian volume per ovary (P < 0.001) and the total number of antral follicles per ovary (P < 0.001). The control group had significantly larger ovaries and a significantly higher number of total antral follicles than both group 1 and group 2 survivors (P < 0.05 in all comparisons). Moreover, group 1 survivors had significantly larger ovaries (P = 0.011) and a higher number of total antral follicles (P = 0.001) than group 2 survivors.
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Survivors with spontaneous cycles, who were cured with bone-marrow transplantation (group 3), had smaller median ovarian volume and a lower median total follicle number than survivors with spontaneous cycles from group 1 and group 2. The results, however, were not significant, possibly because of small sample size (n = 3).
With regard to hormone levels, we found significant differences only in basal FSH. Thus, group 3 survivors with spontaneous cycles had higher levels than controls and group 1 and group 2 survivors with spontaneous cycles (median levels of 11.4, 6.3, 6.5, and 6.6 IU/liter, respectively) (P < 0.05 in all comparisons).
In survivors with spontaneous cycles, we found a significant correlation between inhibin B and the total number of antral follicles per ovary (rs = 0.3, P = 0.01) and between inhibin B and ovarian volume per ovary (rs = 0.3, P = 0.01). In contrast, we found no significant inverse relation between inhibin B and FSH (rs = -0.06, P = 0.6).
To identify predictors of the total antral follicle count per ovary, stepwise, backward, multiple linear regression analysis was performed using data from all survivors. In the final model, explaining 36% of the variance, predictors were: ovary in irradiation field (ß = -0.40, P < 0.001), alkylating chemotherapy (ß = -0.25, P = 0.01), age at diagnosis (ß = -0.25, P = 0.01), and time period off treatment (ß = -0.19, P = 0.044) (Table 5).
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Discussion |
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At study entry, 17 survivors used HRT because of treatment-induced ovarian failure. The sonographic characteristics of these survivors are similar to those of postmenopausal women in general, because it has been shown that ovarian size rapidly decreases and follicles are absent after the menopause (14, 18). The detection rate of the ovaries was 53% in HRT users, which is in accordance with previously reported percentages ranging from 41–87%, but ovarian volume was smaller (0.2–2.0 cm3) than in postmenopausal women in general (1.2–5.8 cm3) (18). It is unknown whether the greater reduction in ovarian volume is second to anticancer therapy. As expected, FSH and LH levels were elevated in the HRT users, indicating ovarian failure. Estradiol levels, however, were significantly higher in HRT users, compared with controls, OC users, and survivors with spontaneous menstrual cycles. The explanation may be that, although the estrogenic component in the postmenopausal hormone therapy is administered cyclically, the daily doses induce relatively high serum levels.
It is generally accepted that the age-related decline in the resting follicle pool is closely related to female reproductive aging. After a period of optimal fertility, from approximately 18–30 yr of age, the progressive loss of primordial follicles leads to a 10-yr period of decreased fertility. Cessation of fertility occurs at a mean age of 41 yr, although menstrual cycles are still regular and ovulatory until a mean age of 46 yr (19). An adequate single test to assess the reproductive status of an individual woman has not yet been established, but the number of antral follicles and ovarian volume measured by transvaginal sonography have been shown to correlate with chronological age (13, 14). Thus, our sonographic findings suggest that survivors with spontaneous menstrual cycles have an advanced ovarian age. Both ovarian volumes and antral follicle counts were significantly lower than in the controls. Pavlik et al. (14) reported that mean ovarian volume decreases from 6.6 cm3 in women less than 30 yr of age to 4.8 cm3 in women 40–49 yr old. In women with proven natural fertility, antral follicle numbers have shown to decline from 7–22 at age 30 yr to 2–7 at age 40 yr (13). Although, there may exist unknown ovarian repair mechanisms after anticancer treatment, these data suggest that the biological ovarian age in childhood cancer survivors could be approximately 10 yr ahead of their chronological age. Consequently, the period of decreased fertility and end of fertility may occur much earlier than previously anticipated. This finding suggests that adult female childhood cancer survivors should be informed of their risk of premature cessation of fertility, even in cases of regular menstrual cycles, which erroneously indicate a normal ovarian potential.
Our results regarding early follicular-phase inhibin B levels also indicate an advanced reproductive age. Thus, survivors with spontaneous menstrual cycles had significantly lower inhibin B levels, compared with the control group. Welt et al. (20) reported a decreased inhibin B secretion in cycling women of 35 yr of age or more with normal d 3 FSH, compared with women less than 35 yr of age, and this suggested that a decrease in inhibin B level may be the earliest endocrine marker of the decline in antral follicle number with reproductive aging. In accordance with our findings, they reported that the significant decrease in inhibin B levels occurred in concert with a significant increase in estradiol levels. Elevated basal estradiol levels are a result of follicular recruitment already in the late luteal phase of the preceding menstrual cycle and thus an advanced development of a dominant follicle, which produces increasing amounts of estrogen in the early follicular phase. These cycle characteristics are commonly seen in women of advanced reproductive age. Further, it has been argued that elevated estradiol levels may be able to suppress FSH into the normal range in women who have a diminished ovarian reserve (21). This could account for similar basal FSH levels when all survivors with spontaneous menstrual cycles were compared with the controls. It has, however, also been suggested that basal FSH is not a good marker for the gradual loss of ovarian functional capacity, because it presumably only increases above the normal range with severe loss of ovarian function (22).
Ovarian volume differed significantly between OC users and survivors with spontaneous menstrual cycles, probably because OC reduces the volumes of both ovaries in all phases of the cycle (23). On the contrary, the number of antral follicles was without statistical differences when OC users were compared with survivors with spontaneous cycles. Although OC can suppress FSH sufficiently to prevent the development of a dominant follicle, the number of antral follicles less than 10 mm during the pill-free week may not be altered (24). Thus, the number of antral follicles measured by sonography in the pill-free week may be used to evaluate ovarian function in survivors using OC.
OC users and survivors with spontaneous menstrual cycles had significantly larger ovaries and a significantly higher number of antral follicles, compared with survivors using HRT. Although it is highly plausible that this finding may be explained by the menopausal status (14, 18), it is noteworthy that HRT users were significantly older at study inclusion than OC users and survivors with spontaneous menstrual cycles. Hence, the sonographic findings may be partially explained by the older age in the HRT users, because ovarian volume and antral follicle numbers have been shown to correlate with chronological age (13, 14).
The division of survivors, according to treatment (Table 1), was based on the presumed ovarian toxicity. Alkylating agents and radiotherapy below the diaphragm have previously been shown to carry a considerable risk of inducing an early menopause, and conditioning regimens given before bone-marrow transplantation induce immediate ovarian failure at a very high rate (8, 9, 10, 11, 25). We have shown a gradual and significant decrease in ovarian volume and antral follicle numbers in relation to treatment-groups, supporting current knowledge regarding potential gonadotoxic chemotherapy and radiotherapy. It is, however, noteworthy that our endpoint was not only whether or not ovarian failure had occurred but also the degree of ovarian follicular depletion in survivors with spontaneous menstrual cycles. The results suggest that treatment modalities should be taken into account if female survivors seek fertility counseling, also because alkylating chemotherapy and direct ovarian irradiation were the most important predictors of the total antral follicle count. Surprisingly, group 1 patients, of whom none had received alkylating chemotherapy or irradiation below the diaphragm, had significantly smaller ovaries and fewer antral follicles, compared with the control group, suggesting that nonalkylating chemotherapy also has some gonadotoxic effect. Unfortunately, the size of the cohort and the multiagent regimens applied to the vast majority of the survivors did not allow dose-toxicity analyses to clarify the impact on ovarian reserve from specific chemotherapeutic agents.
We did not have an upper age limit for participation in this population-based research program. Therefore, the age range at study inclusion was rather wide. Our results showed that the OC users represented the youngest survivors and the HRT users represented the oldest. Indeed, the HRT users were significantly older than OC users and survivors with spontaneous cycles. We did not stratify for age, because median ages were alike when all 100 survivors were compared with controls, and because median ages and range were similar in survivors with spontaneous cycles and controls, in whom the most comparisons were made.
It can be questioned whether the control group is a representative sample of young healthy women. However, our sonographic findings in the controls are very similar to previous published data in women younger than 30 yr of age (13, 14).
Transvaginal ovarian sonography permits precise and reproducible measurements of the ovarian volume and the total antral follicle count (26, 27). In the current study, the same investigator performed all the ultrasound examinations. Although, this may have affected the results, it has also limited interobserver variability and should not influence the significant differences in ovarian volume and follicle counts.
Fertility counseling of female childhood cancer survivors is difficult, in part, because they have not yet reached ages at which the lifetime impact of therapy can be evaluated, but also because treatment has differed with time. Today, there is a tendency toward an intensification of treatment emphasizing the need for close and regular follow-up. Our results suggest that, besides knowledge of previous treatment ovarian sonography and inhibin B levels may be used as serial tests to identify those women with a normal spontaneous menstrual cycle and normal FSH who may have subclinical ovarian damage and thus an increased risk of early cessation of fertility.
In conclusion, this population-based study has shown that anticancer treatment in childhood may have severe, lasting adverse effects on ovarian function. Clinicians should be aware of a possible increased risk of subfertility caused by a diminished ovarian reserve and should not delay fertility counseling.
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Footnotes |
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Abbreviations: CV, Coefficient of variation; HRT, hormonal replacement therapy; OC, oral contraceptives; PRL, prolactin; rs, correlation coefficient.
Received February 28, 2003.
Accepted August 7, 2003.
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W. Chemaitilly, A. C. Mertens, P. Mitby, J. Whitton, M. Stovall, Y. Yasui, L. L. Robison, and C. A. Sklar Acute Ovarian Failure in the Childhood Cancer Survivor Study J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1723 - 1728. [Abstract] [Full Text] [PDF]
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 M. Sonmezer and K. Oktay Fertility preservation in young women undergoing breast cancer therapy. Oncologist, May 1, 2006; 11(5): 422 - 434. [Abstract] [Full Text] [PDF]
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K.L.T. Schmidt, C. Y. Andersen, A. Loft, A.G. Byskov, E. Ernst, and A. N. Andersen Follow-up of ovarian function post-chemotherapy following ovarian cryopreservation and transplantation Hum. Reprod., December 1, 2005; 20(12): 3539 - 3546. [Abstract] [Full Text] [PDF]
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K. Behringer, K. Breuer, T. Reineke, M. May, L. Nogova, B. Klimm, T. Schmitz, L. Wildt, V. Diehl, and A. Engert Secondary Amenorrhea After Hodgkin's Lymphoma Is Influenced by Age at Treatment, Stage of Disease, Chemotherapy Regimen, and the Use of Oral Contraceptives During Therapy: A Report From the German Hodgkin's Lymphoma Study Group J. Clin. Oncol., October 20, 2005; 23(30): 7555 - 7564. [Abstract] [Full Text] [PDF]
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A. Weghofer, M. Margreiter, Y. Fauster, T. Schaetz, A. Brandstetter, D. Boehm, and W. Feichtinger Age-specific FSH levels as a tool for appropriate patient counselling in assisted reproduction Hum. Reprod., September 1, 2005; 20(9): 2448 - 2452. [Abstract] [Full Text] [PDF]
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 R. A. Lobo Potential Options for Preservation of Fertility in Women N. Engl. J. Med., July 7, 2005; 353(1): 64 - 73. [Full Text] [PDF]
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 C. Sklar Maintenance of Ovarian Function and Risk of Premature Menopause Related to Cancer Treatment J Natl Cancer Inst Monographs, March 1, 2005; 2005(34): 25 - 27. [Abstract] [Full Text] [PDF]
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K. Lutchman Singh, M. Davies, and R. Chatterjee Fertility in female cancer survivors: pathophysiology, preservation and the role of ovarian reserve testing Hum. Reprod. Update, January 1, 2005; 11(1): 69 - 89. [Abstract] [Full Text] [PDF]
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M. Sonmezer and K. Oktay Fertility preservation in female patients Hum. Reprod. Update, May 1, 2004; 10(3): 251 - 266. [Abstract] [Full Text] [PDF]
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