Johnston RJ, Wallace WH.. Normal ovarian function and assessment of ovarian reserve in the survivor of childhood cancer. Pediatr Blood Cancer 53: 296-302
Royal Hospital for Sick Children, Edinburgh, Scotland, United Kingdom. Pediatric Blood & Cancer
(Impact Factor: 2.39).
08/2009; 53(2):296-302. DOI: 10.1002/pbc.22012
Increasingly young people survive cancer in childhood and as a result complications of its treatment are becoming more common and important. Premature ovarian failure is recognized as a complication of radiotherapy to a field that includes the pelvis and alkylating-agent-based chemotherapy. Young pre-pubertal girls are not protected from the effects of gonadal toxic therapy. A young woman, successfully treated for cancer during childhood, may experience regular periods in the presence of a significantly reduced ovarian reserve. There is, however, no reliable measure of ovarian reserve available for the individual woman. Assessment of ovarian function relies on the use of surrogate markers such as follicle stimulating hormone, inhibin-B, and anti-mullerian hormone as well as ultrasound assessment of ovarian volume and antral follicle count. We discuss the physiology of normal ovarian function, the effects of cancer treatments on ovarian function and the techniques for evaluation of ovarian reserve in survivors of childhood cancer.
Available from: Elon Roti Roti
- "The stroma and theca cells are the only ovarian cells in direct contact with systemic circulation. Numerous studies have shown follicle and oocyte attrition following chemotherapy , , , , , , , , but it is unclear whether oocytes are directly targeted by the anti-cancer process, or deteriorate as the surrounding follicular cells fail. "
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ABSTRACT: Primary ovarian insufficiency (POI) is one of the many unintended consequences of chemotherapy faced by the growing number of female cancer survivors. While ovarian repercussions of chemotherapy have long been recognized, the acute insult phase and primary sites of damage are not well-studied, hampering efforts to design effective intervention therapies to protect the ovary. Utilizing doxorubicin (DXR) as a model chemotherapy agent, we defined the acute timeline for drug accumulation, induced DNA damage, and subsequent cellular and follicular demise in the mouse ovary. DXR accumulated first in the core ovarian stroma cells, then redistributed outwards into the cortex and follicles in a time-dependent manner, without further increase in total ovarian drug levels after four hours post-injection. Consistent with early drug accumulation and intimate interactions with the blood supply, stroma cell-enriched populations exhibited an earlier DNA damage response (measurable at 2 hours) than granulosa cells (measurable at 4 hours), as quantified by the comet assay. Granulosa cell-enriched populations were more sensitive however, responding with greater levels of DNA damage. The oocyte DNA damage response was delayed, and not measurable above background until 10-12 hours post-DXR injection. By 8 hours post-DXR injection and prior to the oocyte DNA damage response, the number of primary, secondary, and antral follicles exhibiting TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive granulosa cells plateaued, indicating late-stage apoptosis and suggesting damage to the oocytes is subsequent to somatic cell failure. Primordial follicles accumulate significant DXR by 4 hours post-injection, but do not exhibit TUNEL-positive granulosa cells until 48 hours post-injection, indicating delayed demise. Taken together, the data suggest effective intervention therapies designed to protect the ovary from chemotherapy accumulation and induced insult in the ovary must act almost immediately to prevent acute insult as significant damage was seen in stroma cells within the first two hours.
Available from: Richard J Cohn
- "Additional to scatter from lumbar-sacral radiation, the ovaries can also be irradiated directly as part of abdominal, pelvic, or total body irradiation. Premature ovarian failure may take the form of either acute ovarian failure (AOF), where there is a loss of ovarian function during or shortly after the completion of cancer therapy, or premature menopause, defined as menopause younger than 40 years in survivors who retain ovarian function following treatment [28, 33]. The specific risk of premature ovarian failure after direct radiation to the ovaries is site and dose-dependent [28, 34]. "
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ABSTRACT: Childhood cancer treatments can cause female reproductive late effects. Radiation to the hypothalamic-pituitary-ovarian axis is associated with altered menarche, miscarriage, and implantation failure. Patients who receive chemotherapy and/or ovarian radiation are at risk of premature ovarian failure; the risk increases with increasing radiation dose, alkylating agent score, combination therapy, and older age at treatment. Ovarian reserve may be assessed using antimullerian hormone assay and ultrasound measurements of ovarian volume and antral follicle count; however, their efficacy is poorly established in this cohort. Fertility preservation options including cryopreservation, oophoropexy, and gonadotropin-releasing hormone analogues may be initiated prior to treatment, although most are still considered experimental. Uterine radiation has been linked to pregnancy complications including miscarriage, premature delivery, stillbirth, low-birth-weight and small-for-gestational-age infants. This paper summarises the literature on female reproductive late effects. The information should facilitate counseling and management of female survivors throughout their reproductive lives.
Available from: nature.com
- "Fertility preservation is an increasingly urgent issue for female cancer survivors (Backhus et al., 2007; Dunn and Fox, 2009; Hulvat and Jeruss, 2009; Johnston and Wallace, 2009; Maltaris et al., 2009; Peate et al., 2009; Jeruss and Woodruff, 2009; Woodruff, 2009; van der Kaaij et al., 2010; Gardino et al., 2010). This is also due to rapid advances in reproductive technologies (Maltaris et al., 2008; West et al., 2009). "
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ABSTRACT: Cells experiencing DNA damage undergo a complex response entailing cell-cycle arrest, DNA repair and apoptosis, the relative importance of the three being modulated by the extent of the lesion. The observation that Abl interacts in the nucleus with several proteins involved in different aspects of DNA repair has led to the hypothesis that this kinase is part of the damage-sensing mechanism. However, the mechanistic details underlying the role of Abl in DNA repair remain unclear. Here, I will review the evidence supporting our current understanding of Abl activation following DNA insults, while focusing on the relevance of these mechanisms in protecting DNA-injured germ cells. Early studies have shown that Abl transcripts are highly expressed in the germ line. Abl-deficient mice exhibit multiple abnormalities, increased perinatal mortality and reduced fertility. Recent findings have implicated Abl in a cisplatin-induced signaling pathway eliciting death of immature oocytes. A p53-related protein, TAp63, is an important immediate downstream effector of this pathway. Of note, pharmacological inhibition of Abl protects the ovarian reserve from the toxic effects of cisplatin. This suggests that the extent of Abl catalytic outputs may shift the balance between survival (likely through DNA repair) and activation of a death response. Taken together, these observations are consistent with the evolutionary conserved relationship between DNA damage and activation of the p53 family of transcription factors, while shedding light on the key role of Abl in dictating the fate of germ cells upon genotoxic insults.
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