Premature Ovarian Insufficiency in Childhood Cancer Survivors: A Report From the St. Jude Lifetime Cohort

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Abstract

<div class="section"> <a class="named-anchor" id="s1">  </a> <h5 class="section-title" id="d9456323e404">Context:</h5> <p id="d9456323e406">Long-term follow-up data on premature ovarian insufficiency (POI) in childhood cancer survivors are limited. </p> </div><div class="section"> <a class="named-anchor" id="s2">  </a> <h5 class="section-title" id="d9456323e409">Objective:</h5> <p id="d9456323e411">To describe the prevalence of POI, its risk factors, and associated long-term adverse health outcomes. </p> </div><div class="section"> <a class="named-anchor" id="s3">  </a> <h5 class="section-title" id="d9456323e414">Design:</h5> <p id="d9456323e416">Cross-sectional.</p> </div><div class="section"> <a class="named-anchor" id="s4">  </a> <h5 class="section-title" id="d9456323e419">Setting:</h5> <p id="d9456323e421">The St. Jude Lifetime Cohort Study, an established cohort in a tertiary care center.</p> </div><div class="section"> <a class="named-anchor" id="s5">  </a> <h5 class="section-title" id="d9456323e424">Patients:</h5> <p id="d9456323e426">Nine hundred twenty-one participants (median age, 31.7 years) were evaluated at a median of 24.0 years after cancer diagnosis. </p> </div><div class="section"> <a class="named-anchor" id="s6">  </a> <h5 class="section-title" id="d9456323e429">Main Outcome Measure:</h5> <p id="d9456323e431">POI was defined by persistent amenorrhea combined with a follicle-stimulating hormone level >30 IU/L before age 40. Multivariable Cox regression was used to study associations between demographic or treatment-related risk factors and POI. Multivariable logistic regression was used to study associations between POI and markers for cardiovascular disease, bone mineral density (BMD), and frailty. Exposure to alkylating agents was quantified using the validated cyclophosphamide equivalent dose (CED). </p> </div><div class="section"> <a class="named-anchor" id="s7">  </a> <h5 class="section-title" id="d9456323e434">Results:</h5> <p id="d9456323e436">The prevalence of POI was 10.9%. Independent risk factors for POI included ovarian radiotherapy at any dose and CED ≥8000 mg/m <sup>2</sup>. Patients with a body mass index ≥30 kg/m <sup>2</sup> at the time of the St. Jude Lifetime Cohort assessment were less likely to have a diagnosis of POI. Low BMD and frailty were independently associated with POI. </p> </div><div class="section"> <a class="named-anchor" id="s8">  </a> <h5 class="section-title" id="d9456323e445">Conclusion:</h5> <p id="d9456323e447">High-dose alkylating agents and ovarian radiotherapy at any dose are associated with POI. Patients at the highest risk should be offered fertility preservation whenever feasible. POI contributes to poor general health outcomes in childhood cancer survivors; further studies are needed to investigate the role of sex hormone replacement in improving such outcomes. </p> </div><p class="first" id="d9456323e450">We report on the prevalence, risk factors, and consequences on general health of premature ovarian insufficiency in a cohort of 921 long-term survivors of childhood cancers. </p>

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Predicting age of ovarian failure after radiation to a field that includes the ovaries.

Douglas W R Wallace, Thomas Kelsey, Frank Saran … (2005)

To predict the age at which ovarian failure is likely to develop after radiation to a field that includes the ovary in women treated for cancer. Modern computed tomography radiotherapy planning allows determination of the effective dose of radiation received by the ovaries. Together with our recent assessment of the radiosensitivity of the human oocyte, the effective surviving fraction of primordial oocytes can be determined and the age of ovarian failure, with 95% confidence limits, predicted for any given dose of radiotherapy. The effective sterilizing dose (ESD: dose of fractionated radiotherapy [Gy] at which premature ovarian failure occurs immediately after treatment in 97.5% of patients) decreases with increasing age at treatment. ESD at birth is 20.3 Gy; at 10 years 18.4 Gy, at 20 years 16.5 Gy, and at 30 years 14.3 Gy. We have calculated 95% confidence limits for age at premature ovarian failure for estimated radiation doses to the ovary from 1 Gy to the ESD from birth to 50 years. We report the first model to reliably predict the age of ovarian failure after treatment with a known dose of radiotherapy. Clinical application of this model will enable physicians to counsel women on their reproductive potential following successful treatment.

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Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: a report from the St Jude Lifetime cohort study.

Kirsten K Ness, Kevin R. Krull, Kendra Jones … (2013)

Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality.

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Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults.

Richard A Anderson, Rod T. Mitchell, Thomas Kelsey … (2015)

Preservation of gonadal function is an important priority for the long-term health of cancer survivors of both sexes and all ages at treatment. Loss of opportunity for fertility is a prime concern in both male and female cancer survivors, but endocrine effects of gonadal damage are likewise central to long-term health and wellbeing. Some fertility preservation techniques, such as semen and embryo cryopreservation, are established and successful in adults, and development of oocyte vitrification has greatly improved the potential to cryopreserve unfertilised oocytes. Despite being recommended for all pubertal male patients, sperm banking is not universally practised in paediatric oncology centres, and very few adolescent-friendly facilities exist. All approaches to fertility preservation have specific challenges in children and teenagers, including ethical, practical, and scientific issues. For young women, cryopreservation of ovarian cortical tissue with later replacement has resulted in at least 40 livebirths, but is still regarded as experimental in most countries. For prepubertal boys, testicular biopsy cryopreservation is offered in some centres, but how that tissue might be used in the future is unclear, and so far no evidence suggests that fertility can be restored. For both sexes, these approaches involve an invasive procedure and have an uncertain risk of tissue contamination in haematological and other malignancies. Decision making for all these approaches needs assessment of the individual's risk of fertility loss, and is made at a time of emotional distress. Development of this specialty needs better provision of information for patients and their medical teams, and improvements in service provision, to match technical and scientific advances.