1 Department of Reproductive and Developmental Sciences, University of Edinburgh, 2 Department of Obstetrics and Gynaecology, Fife Acute Hospitals NHS Trust and 3 MRC Human Reproductive Sciences Unit, Edinburgh, UK
4 To whom correspondence should be addressed. Email: hamish.wallace{at}luht.scot.nhs.uk
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Abstract |
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Key words: childhood cancer/ovarian cryopreservation/ovarian failure/pelvic tumour/radiotherapy
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Introduction |
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For young people at risk of ovarian failure following chemotherapy or radiotherapy, the options for fertility preservation are limited (Wallace et al., 2004). Strategies for preserving reproductive potential include storage of embryos and mature oocytes, which is only possible in post-pubertal women. For the young female, ovarian cortical tissue rich in primordial follicles may be cryopreserved (Poirot et al., 2002
). Successful return of ovarian function following reimplantation of cortical strips has been reported in ovariectomized sheep with subsequent conception (Gosden et al., 1994
). Reimplantation and limited return of ovarian activity has been reported in a woman who had received gonadal toxic therapy before ovarian tissue collection (Radford et al., 2001
). Spontaneous ovulation and pregnancy remain possible in women with premature ovarian failure (Nasir et al., 1997
; Kalantaridou and Nelson, 2000
). Ovarian activity and particularly pregnancy following cryopreservation and reimplantation must therefore be carefully documented not to be derived from residual ovarian tissue even after clearly demonstrated ovarian failure. We here report such a case.
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Case report |
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Ovarian function was monitored during and after treatment. After completion of radiotherapy aged 15.3 years, she developed symptoms and biochemical evidence of ovarian failure with hot flushes, elevated gonadotrophins and undetectable inhibin B concentrations in serum (see Table I). Sex steroid replacement in the form of the combined oral contraceptive pill, Loestrin 20 (ethinyl estradiol 20 µg and norethisterone acetate 1 mg) was commenced and continued until completion of chemotherapy. There was intermittent vaginal spotting and HRT was discontinued for 3 months on completion of treatment. Re-evaluation of her biochemical data confirmed ovarian failure with significant elevation of serum gonadotrophins and undetectable inhibin B with absent menses (Table I). HRT was restarted but persistent vaginal bleeding continued. A variety of preparations was administered, as detailed in Figure 1. Aged 16.7 years, while on HRT, a transabdominal ultrasound scan of her pelvis demonstrated a uterine length of 5.9 cm (AP 2.6 cm, transverse 3 cm) with an endometrial echo. Wave forms were obtained from both uterine arteries: the left had a pulsatility index of 2.72 and the right 2.87. The left ovarian volume was 2.2 ml and the right 4.2 ml. No follicles were seen and no Doppler signals were obtained from either ovary. HRT was discontinued for 3 weeks, after which gonadotrophin levels indicated ovarian failure (see Figure 1). Continuous transdermal estradiol with oral progesterone every 2 weeks for 14 days was then recommenced. Further evaluation of the persistent vaginal bleeding, on the above regimen, at the age of 18.5 years included an examination under anaesthesia, a cervical smear, a biopsy of vaginal wall, a hysteroscopy and an endometrial biopsy. Examination revealed an atrophic lower vaginal tract. Biopsy of the vaginal wall showed chronic inflammation and ulceration consistent with a post-radiation effect. The uterine cavity appeared normal and the endometrial biopsy showed normal early secretory phase endometrium. Radiation damage to the lower vaginal tract was found to be the cause for the bleeding and topical vaginal estrogen was prescribed in addition to transdermal estradiol. The intermittent vaginal bleeding improved.
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An ultrasound scan carried out when she was 20.2 years, following a history of abdominal pain and vaginal bleeding, demonstrated an early intrauterine pregnancy. The bleeding resolved and the pregnancy progressed. Cardiac assessment was carried out to exclude anthracycline cardiomyopathy. Pelvic assessment was required to consider optimum mode of delivery in view of previous pelvic mass and radiotherapy. Regular fetal growth assessments were performed in view of concern of potential effect of radiotherapy on uterine function. Fetal growth progressed normally.
The history of pelvic radiotherapy suggested that vaginal delivery might be difficult and a decision was made to proceed to elective Caesarean section. At 38 weeks gestation, a healthy baby boy was delivered weighing 2940 g (3rd10th centile). Intraoperative examination of the pelvic structures revealed apparently normal ovaries and pelvic bones with no macroscopic evidence of radiation damage.
After delivery there was spontaneous return of menses. Menses have remained regular over the subsequent 15 months, without any HRT. Early follicular gonadotrophin levels were initially normal but more recently have indicated impaired ovarian function, with plasma inhibin B remaining undetectable (see Table I). A pelvic ultrasound scan 15 months after delivery showed uterine length to be 7.3 cm (AP 3.7 cm, transverse 5.3 cm). The uterine artery blood flow was normal. The left ovary was not seen. The right ovary measured 1.9 x 1.8 x 1.5 cm (volume 2.3 ml).
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Discussion |
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The risk of ovarian failure should be assessed before potentially gonadal toxic treatment begins and discussed with the patient and family. Exact prediction is not possible as this case demonstrates, but fertility preservation should be discussed with those deemed at high risk of ovarian failure. For pre-pubertal girls, and the majority of young women, preservation of fertility remains experimental and harvesting and storage of gonadal tissue before commencing cancer therapy is the most promising option (Grundy et al., 2001; Multidisciplinary Working Group, 2003
).
Incipient ovarian failure may be detected by early follicular biochemical assessment of serum gonadotrophin and inhibin B concentrations (Creus et al., 2000). Recently anti-Müllerian hormone has been shown to be a potential marker of ovarian reserve (de Vet et al., 2002
; Bath et al., 2003
). Radiological assessment of ovarian volume may also be a potential predictor of reserve, with ovarian volume correlating with number of remaining follicles (Syrop et al., 1999
; Larsen et al., 2003
, Wallace et al., 2004
).
Return of ovarian function and conception years after gonadal toxic chemotherapy and biochemical evidence of ovarian failure has been reported previously (Nasir et al., 1997). There are few reports of return of ovarian function after radiation-induced ovarian failure (Chao et al., 1998
). Early data from autopsy specimens of children with leukaemia demonstrated a reduction in antral follicle number following chemotherapy (Himmelstein-Braw et al., 1978). Return of ovarian activity several months after completion of therapy and after documented biochemical ovarian failure is well recognized and reflects the duration of follicular growth from the primordial stage (Gougeon, 1996
). The basis for return of ovarian activity years after documented evidence of ovarian failure is unclear. Women with premature ovarian failure after gonadal toxic therapy should be aware of the small but possible chance of return of function and therefore conception.
Collection of ovarian tissue as a potential method of preserving reproductive potential is available in some centres, and there is increasing evidence for the potential for partial restoration of ovarian function by heterotopic (Lee et al., 2004; Oktay et al., 2004
) and orthotopic (Oktay and Karlikaya, 2001; Radford et al., 2001
; Tryde Schmidt et al., 2004
) transplantation. Recently, a spontaneous pregnancy after orthotopic ovarian transplantation in a Hodgkin survivor was also reported (Donnez et al., 2004). In these cases, consideration had been given to reimplantation as fertility was not thought possible, given the clinical and biochemical evidence of ovarian failure. However, in the case of orthotopic transplantation, the spontaneous conception could have then been erroneously attributed to successful re-engraftment and function of the stored cortical tissue. This case report thus clearly illustrates the need for precise analysis of the possible functional activity of any reimplanted ovarian tissue, particularly when reimplanted adjacent to or on existing ovary.
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References |
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Submitted on April 5, 2004; resubmitted on July 12, 2004; accepted on July 21, 2004.