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      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"> <!-- named anchor --> </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"> <!-- named anchor --> </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"> <!-- named anchor --> </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"> <!-- named anchor --> </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"> <!-- named anchor --> </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"> <!-- named anchor --> </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 &gt;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"> <!-- named anchor --> </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"> <!-- named anchor --> </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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          Most cited references22

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

          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.

            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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              Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study.

              These studies were undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on ovarian function and reproductive outcomes. We reviewed the frequency of acute ovarian failure, premature menopause, live birth, stillbirth, spontaneous and therapeutic abortion and birth defects in the participants in the Childhood Cancer Survivor Study (CCSS). Acute ovarian failure (AOF) occurred in 6.3% of eligible survivors. Exposure of the ovaries to high-dose radiation (especially over 10 Gy), alkylating agents and procarbazine, at older ages, were significant risk factors for AOF. Premature nonsurgical menopause (PM) occurred in 8% of participants versus 0.8% of siblings (rate ratio = 13.21; 95% CI, 3.26 to 53.51; P < .001). Risk factors for PM included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score, and a diagnosis of Hodgkin's lymphoma. One thousand two hundred twenty-seven male survivors reported they sired 2,323 pregnancies, and 1,915 female survivors reported 4,029 pregnancies. Offspring of women who received uterine radiation doses of more than 5 Gy were more likely to be small for gestational age (birthweight < 10 percentile for gestational age; 18.2% v 7.8%; odds ratio = 4.0; 95% CI, 1.6 to 9.8; P = .003). There were no differences in the proportion of offspring with simple malformations, cytogenetic syndromes, or single-gene defects. These studies demonstrated that women treated with pelvic irradiation and/or increasing alkylating agent doses were at risk for acute ovarian failure, premature menopause, and small-for-gestational-age offspring. There was no evidence for an increased risk of congenital malformations. Survivors should be generally reassured although some women have to consider their potentially shortened fertile life span in making educational and career choices.
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                Author and article information

                Journal
                The Journal of Clinical Endocrinology & Metabolism
                The Endocrine Society
                0021-972X
                1945-7197
                July 01 2017
                July 01 2017
                : 102
                : 7
                : 2242-2250
                Article
                10.1210/jc.2016-3723
                5505200
                28368472
                0772dad0-dd2f-42ac-a456-a5a423772c65
                © 2017
                History

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