Human Reproduction, Vol. 18, No. 2, 417-422,
February 2003
© 2003 European Society of Human Reproduction and Embryology
Diminished ovarian reserve in female childhood cancer survivors with regular menstrual cycles and basal FSH <10 IU/l
1 Fertility Clinic, 2 Department of Growth and Reproduction, 3 Pediatric clinic II and 4 Department of Pediatrics, The Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark
5 To whom correspondence should be addressed. e-mail: elisabeth.larsen{at}dadlnet.dk
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Abstract |
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BACKGROUND: Approximately 70% of children treated for cancer are cured, however the treatment often impairs reproductive function. The aim of the present study was to assess ovarian reserve in women with an apparently normal ovarian function, who were cured of cancer in childhood. METHODS: Twenty-one female survivors with regular menstrual cycles and basal FSH <10 IU/l were included. The control group included 21 healthy age-matched regularly cycling women. On cycle day 2–5, ovarian volume and number of small antral follicles (2–5 mm) were evaluated with transvaginal ultrasonography. Repeated sonography, urinary LH testing, and endocrine assessments were performed during the actual cycle. Cycle length was calculated. RESULTS: The female survivors had significantly smaller volume per ovary (4.9 versus 6.8 cm3; P < 0.01), a lower number of small antral follicles per ovary (4.5 versus 8.0; P < 0.01), and lower total number of follicles per ovary (8 versus 11, P < 0.01). Hormonal profiles were similar, but the mean cycle length of the female survivors was significantly shorter than in the control group (28.3 versus 31.0 days; P < 0.05). CONCLUSIONS: Childhood cancer survivors with regular menstrual cycles and basal FSH <10 IU/l seem to have a diminished ovarian reserve. Consequently, they may have a shortened reproductive span and an early menopause.
Key words: basal FSH/childhood cancer/early menopause/ovarian reserve
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The 5 year survival rate for children treated for a malignant disease has increased to >70% during the last three decades, primarily due to an improvement in combinations of surgery, radiotherapy, and intensive multi-agent chemotherapy (Landis et al., 1998
). However, adult long-term survivors of childhood cancer often suffer from late effects of the disease and treatment, and in female survivors an early menopause is an important and burdening side-effect of curative chemo- and radiotherapy (Levy and Stillman, 1991; Levitt and Jenney, 1998). As the majority of women cured of cancer in childhood expect a normal reproductive life span, an early loss of fertility can seriously harm their quality of life.
The cancer treatments causing ovarian damage are primarily alkylating chemotherapy and radiotherapy to the gonads (Howell and Shalet, 1998; Meirow and Nugent, 2001; Bath et al., 2002). Animal studies have shown that both alkylating agents and radiotherapy destroy ovarian primordial follicles in a dose-related manner, leading to either immediate ovarian failure or an early menopause (Gosden et al., 1997; Meirow et al., 1999).
Although women treated for cancer in childhood and not least adolescence may have an increased risk of an early menopause (Byrne et al., 1992; Chiarelli et al., 1999), several studies have found that a proportion of female survivors have normal endocrine profiles including FSH, menstrual histories, and fertility (Sy Ortin et al., 1990; Hudson et al., 1993; Wallace et al., 1993; Papadakis et al., 1999). However, these parameters may be insufficient to predict ovarian reserve, as exposure to chemotherapy that destroys half of the ovarian primordial follicle reserve in mice does not affect ovulation, mating, and short-term pregnancy rates (Meirow et al., 1999).
Assessment of ovarian reserve is a valuable tool when predicting outcome after assisted reproduction techniques. Sonographic measurement of ovarian volume and antral follicle counts have been shown to be important predictors of success in the treatment of infertility as well as early and specific indicators of normal ovarian ageing (Lass et al., 1997; Chang et al., 1998; Scheffer et al., 1999; Pavlik et al., 2000; de Boer et al., 2002)
To our knowledge, no previous study has described ovarian reserve in female childhood cancer survivors. We hypothesize that although the childhood cancer survivor has an apparently normal ovarian function, the ovarian reserve may be altered due to treatment and/or disease. The aim of the present study was to assess ovarian reserve in the early follicular phase in women cured of childhood cancer with regular menstrual cycles and basal FSH <10 IU/l.
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Materials and methods |
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The present study is part of a research programme describing ovarian function and fertility potential in women diagnosed with cancer before the age of 15 years at Rigshospitalet, Copenhagen, Denmark from January 1970 through December 1996, who were treated with radiotherapy and/or chemotherapy, and who were aged >18.0 years at the time of study inclusion. Of the 165 patients who fulfilled the above criteria, 40 were regarded ineligible as 13 lived outside Denmark, 18 were lost for follow-up, five had had a hysterectomy, and four had severe mental disorders and were institutionalized. Twenty-five refused to participate in the research programme. Of the remaining 100 patients, 33 were not eligible for the present study due to known ovarian failure (n = 17), irregular menstrual cycles with a cycle length of >35 days (n = 7), pregnancy (n = 1), or basal FSH values
10 IU/l despite regular menstrual cycles (n = 8). Of the remaining 67 patients, two could not accept transvaginal ultrasonography, 13 did not want to discontinue oral hormonal contraception, and 31 refused for primarily practical reasons, as the study required three or four visits during a menstrual cycle (Figure 1). Thus, 21 patients were studied. A control group was recruited comprising 21 regularly cycling women matched for age. None of the 42 participating women had used hormonal contraception in the preceding 3 months, and none had had previous unilateral or partial oophorectomy.
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For all patients we recorded diagnosis, treatment period, and cumulative doses of applied chemo- and radiotherapy.
Patients and controls were examined in the early follicular phase of a menstrual cycle (cycle day 2–5), and repeatedly during the actual cycle. On cycle day 2–5, a full history was taken regarding menarche, menstrual cycle pattern, pregnancies, and deliveries. Height, weight, and pubertal staging were noted. Ovarian size was measured by transvaginal ultrasonography using The Panther type 2002 ADI (B-K Medical, Gentofte, Denmark) with a 6.5 MHz transvaginal probe. The length and height of the ovaries were measured in the sagittal section and the width in the transverse section after a 90° rotation of the transducer. Ovarian volumes were calculated as: d1xd2xd3x0.523, where d1, d2 and d3 are the three maximal longitudinal, anteroposterior, and transverse diameters. The number of small antral follicles 
5 mm and the number of larger antral follicles >5 mm and 10 mm was counted while the transducer was moved from the outer to the inner margin of the ovary. The follicle diameter was calculated as the mean of two perpendicular measurements. Both ovaries were identified in all participants. The same investigator (E.C.L.) performed and videotaped all examinations. Blood samples were analysed for FSH, LH, estradiol, inhibin A and B, testosterone, thyroid-stimulating hormone (TSH), thyroxin, sex hormone-binding globulin (SHBG), and prolactin.
On cycle day 9–11, the transvaginal ultrasonography was repeated to visualize the dominant follicle (defined as a follicle with a diameter 12 mm). FSH, estradiol, progesterone and inhibin A and B were analysed. If a dominant follicle had not developed on cycle day 9–11, the sonography was repeated on cycle day 14–18. Urine dipsticks detecting LH were recorded daily after the dominant follicle was visible. Seven days after a self-reported LH surge, serum progesterone was analysed to determine whether the cycle was ovulatory (defined as a mid-luteal progesterone concentration of 20 nmol/l). Transvaginal ultrasonography was performed to identify a corpus luteum, if possible. Additionally, inhibin A and inhibin B were analysed.
Finally, cycle length was calculated as the interval (in days) from the first day of menstruation in one cycle to the day prior to day 1 in the next. In the controls, day 1 of the preceding three cycles and day 1 of the actual cycle were noted when they entered the study. Furthermore, they were asked to send in the dates of the next two cycles. In the patients, day 1 of three preceding cycles as well as day 1 of an actual cycle were registered when they entered the research programme (Figure 1). In addition, we registered day 1 of the cycle when they entered the present study as well as day 1 of any cycle between the research programme and the present study. The study was carried out in accordance with Helsinki Declaration II. Informed consent was obtained from the participating women and the protocol was approved by the regional ethical committee (KF) 01-007/99.
Hormone concentration measurements
Hormone concentrations were measured with commercially available kits: FSH, LH, prolactin and thyroxine with AxSym® system (Abbott Labs., Illinois, USA); TSH, SHBG and progesterone with AutoDelfiaTM (Wallac, Turku, Finland); estradiol with Pantex (E2) 125I kit (Pantex, Santa Monica, USA); and testosterone with Coat-a-Count® (Diagnostic Products Corporation, Los Angeles, USA).
AxSym FSH, LH and prolactin are based on microparticle enzyme immunoassay technology. The upper 95% limit of the sensitivity determination for FSH assay, LH assay, and prolactin assay are 0.37 IU/l, 0.5 IU/l and 14.4 mIU/l respectively. AxSym thyroxine is a fluorescence polarization immunoassay with a sensitivity of 1.05 µg T4/dl.
AutoDelfiaTM is a time-resolved fluoro-immunoassay. The intra- and inter-assay coefficient of variation (CV) is <5% for TSH, <8% for SHBG and <2% for progesterone. Pantex (E2) 125I kit measures estradiol in serum using the principles of radioimmunoassay. The sensitivity is 10 pg/ml, the intra-assay CV is 4.3%, and inter-assay CV 5.1%. Coat-a-Count total testosterone is a solid-phase 125I radioimmunoassay with a sensitivity of 0.14 nmol/l.
Serum inhibin A and inhibin B were measured in duplicate in double antibody enzyme immunometric assays (Oxford Bio-Innovation Ltd, Oxford, UK) using monoclonal antibodies raised against the inhibin subunits (
A-chains and B-chains). The detection limits were 7 and 20 pg/ml for inhibin A and inhibin B, respectively. Intra- and inter-assay CV were <15% for inhibin A and <16% for inhibin B.
Urinary LH analysis
Clearplan (Unipath Limited, Bedford, UK), a commercial kit, was used. According to the manufacturers, Clearplan has been shown to be 99% accurate in detecting the LH surge.
Statistical methods
Statistical analysis of the data was performed with SPSS software (Statistical Package for Social Sciences) for Windows, version 10.0. Results are expressed as medians and ranges. The significance of the difference between two groups was estimated using the 
2-test, the Mann–Whitney rank sum test, and two-way analysis of variance. P < 0.05 was accepted as significantly different.
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Results |
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The median age at the time of cancer diagnosis was 6.3 years (range 0.6–13.8 years). At study inclusion, all were in their first remission, and the time interval between the end of treatment and the study inclusion was 16.6 years (4.9–26 years). Ten patients had suffered from solid tumours (non germ cell), and 11 from haematological malignancies. All patients had received chemotherapy that in 12 cases included alkylating agents. Eight of these had also received radiotherapy. Ten patients had radiotherapy at a dose of 18–56 Gy (median 30 Gy) that in no case involved the pelvis. Seven were treated with non-alkylating agents only. All patients had entered puberty spontaneously and were clinically fully matured (breast stage IV or V) at the time of study (Tanner, 1962
). As shown in Table I, the patients and the controls were comparable with regard to age at study inclusion, age at menarche, body mass index (BMI), and cycle day of examination in the early follicular phase. However, mean cycle length was significantly shorter in the patients when compared to the controls (P = 0.028). Additionally, cycle length was analysed using 96 and 90 cycle lengths in the controls and patients respectively. The median number of cycles per control was 5 (3–6) and per patient 4 (3–7). A significant difference was found between the groups (P = 0.026, two-way analysis of variance), which could not be explained from variation within the group. The median coefficient of variance for all participants was 7%, and in no case >14%. The number of pregnancies and deliveries was too low to identify any significant differences.
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Results from the hormone level analyses from cycle day 2–5 are presented in Table II. With regard to FSH, LH, estradiol, inhibin A and B, prolactin testosterone, TSH and SHBG there were no significant differences. Thyroxine was higher in the patients than in the controls but all values were within the normal range [106 (70–168) versus 95 (65–127) nmol/l, P = 0.045].
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Ovarian sonography was normal in all participants on cycle day 2–5, but ovarian volume (P = 0.008), the number of antral follicles
5 mm (P = 0.002), and the total number of follicles 2–10 mm (P = 0.002) differed significantly between the patients and the controls (Table II and Figures 2, 3and 4).
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The results from cycle day 9–11/14–18 and cycle day LH peak +7 showed that two patients did not develop a dominant follicle during the actual cycle. Three patients and 1 control had an insufficient rise in plasma progesterone (2.2–18 nmol/l) despite a dominant follicle being identified at ultrasonography and following a positive urine LH dipstick. This could, however, be due to misinterpretation of the test results of the LH dipstick. With regard to hormonal profiles on cycle day 9–11, we found no differences between patients and controls nor among ovulating participants on cycle day LH peak +7.
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Discussion |
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The present study indicates that even among female childhood cancer survivors with regular menstrual cycles and normal basal FSH, ovarian volume and antral follicle counts are significantly lower compared with age-matched controls.
The age-dependent decline in female fertility is well recognized and presumably determined by a decrease in both oocyte quantity and quality, i.e. ‘the ovarian reserve’ (te Velde et al., 1998). The reduction in ovarian reserve is caused by atresia of ovarian primordial follicles throughout life, and indeed, the antral follicle number present in the early follicular phase most certainly reflects the total ovarian follicular capacity or the reserve (Faddy and Gosden, 1995, 1996). The relationship between increased female age and ovarian ultrasonography is well established. Pavlik et al. (2000) showed in 13 963 women aged 25–91 years a decline in ovarian volume related to age. In women <30 years of age, mean ovarian volume was 6.6 cm3, 6.1 cm3 in women aged 30–39 years, and 4.8 cm3 in women aged 40–49 years. Scheffer et al. (1999) described in women with proven natural fertility a significant correlation between the number of antral follicles (2–10 mm) and age. At the age of 30 years, the follicle number varied from 7 to 22 in the early follicular phase, whereas at age 40 years the range was 2 to 7. Our results could indicate that the ovarian age of female cancer survivors frequently is higher than their chronological age, probably caused by treatment-induced ovarian follicular depletion. As a consequence they may have a shortened reproductive span and an increased risk of entering an early menopause. Figures 2, 3 and 4 show that some female survivors have normal ovarian volumes and follicle numbers. The current study is, however, too small to demonstrate the impact on ovarian reserve of different cancer treatments. This important issue will hopefully be elucidated in the future.
To our knowledge, only two previous studies have described ovarian volume in women cured of childhood cancer (Müller et al., 1996; Bath et al., 2001). Müller et al. (1996) analysed risk factors for gonadal dysfunction, and found that abdominal and transvaginal ultrasonography of the gonads was normal in 21 female patients compared with 11 controls, as there were no differences in measurements of ovarian sizes and follicles. As assessment of ovarian reserve was not the aim of the study, they did not report any data and consequently their results cannot be compared with ours. Bath et al. (2001) assessed hypothalamic–pituitary–ovarian function in 16 controls and in 12 female survivors of childhood acute lymphoblastic leukaemia (ALL) treated with chemotherapy and cranial irradiation. Median age at assessment was 24.1 (17.3–29) and 20.8 (15.8–32.8) years respectively. They found that mean ovarian volume in the ALL group was 4.8 ± 0.54 ml, which was lower but not statistically significant from the controls (5.4 ± 0.57 ml). When compared with our results the difference is in the controls. As our measurements of ovarian volume and total antral follicle counts for healthy women <30 years of age are very similar to the data presented by Pavlik et al. (2000) and Scheffer et al. (1999), we do believe that the controls are representative.
It is known that a woman’s cycle length shortens during reproductive life, as the ovarian follicular depletion accelerates. Treolar et al. (1967), who studied 2700 women for >25 000 woman-years, found a decrease from 30.4 days in women aged 15–24 to 27.7 days in women aged 35–44 years. In 3743 regularly cycling Danish women, similar results were found (Münster et al., 1992). Our data on menstrual cycle length support the results from the transvaginal ultrasonography, namely a possible advancement of ovarian ageing in female childhood cancer survivors.
Despite our strict inclusion criteria there was a trend towards a higher basal FSH and estradiol in the cancer survivors. It has been shown that an elevated early follicular estradiol correlates with reduced ovarian responsiveness in an assisted reproductive treatment programme (Evers et al., 1998). Probably this is due to early follicular recruitment in women who have a diminished ovarian reserve (Buyalos et al., 1998).
As regards the number of cycles where a dominant follicle was identified at sonography and the following LH dipstick was positive, no statistical difference was found between patients and controls. Although this could be explained by small sample size, mice exposed to chemo-agents reducing the primordial follicle reserve by about half have the same ovulation rates as controls (Meirow et al., 1999).
The same investigator performed all the ultrasound examinations, and this may have affected the results, but it has also limited inter-observer variability, and should not influence the differences in ovarian volumes and follicle counts. Additionally, Pache et al. (1990) showed that transvaginal ultrasonography permits precise determinations of the total number of antral follicles 2–10 mm with only little intra-observer variability.
Early follicular levels of FSH and menstrual history may help to identify severe loss of ovarian function. However, these parameters may not be ideal markers in young women at risk of an early menopause, as elevated levels of FSH and cycle irregularities are not permanent before relatively late in the peri-menopausal transition, where achievement of spontaneous and assisted conception is difficult (Speroff et al., 1999). An adequate test to assess the risk of an early menopause has not yet been established, but ovarian sonography could supply knowledge of exposure of gonadotoxic agents and hormonal profile in this particular group of patients.
In conclusion, our findings may reflect the earliest sign of a diminished ovarian reserve in female childhood cancer survivors. Accordingly, they should be advised to try to achieve pregnancy early in adult life rather than postponing childbearing.
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Acknowledgements |
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We gratefully acknowledge a grant from the Children’s Cancer Fund in Denmark and financial support to ECL from the University of Copenhagen, Denmark.
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References |
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Submitted on June 24, 2002; resubmitted on August 30, 2002; accepted on October 30, 2002.
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L.E. Bath, W.H.B. Wallace, M.P. Shaw, C. Fitzpatrick, and R.A. Anderson Depletion of ovarian reserve in young women after treatment for cancer in childhood: detection by anti-Mullerian hormone, inhibin B and ovarian ultrasound Hum. Reprod., November 1, 2003; 18(11): 2368 - 2374. [Abstract] [Full Text] [PDF]
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