Ovarian function and fertility preservation for young people treated for cancer

Further advances in the treatment of young people with cancer have led to improved survival, with 85.6% 5-year relative survival for ages 0–14 in the USA for the years 2010–2016 [18]. However, successful cancer treatment during childhood can cause infertility and premature ovarian insufficiency (POI) in some patients [20, 33]. The risk of developing POI is dependent on a number of factors, which include the nature of the underlying disease and the planned therapy. Both chemotherapy and radiotherapy have been shown to affect ovarian function either directly by depleting the primordial follicle pool or indirectly via effects on hormonal regulation of ovarian function.Postprin

Fertility preservation in pre-pubertal girls with cancer : the role of ovarian tissue cryopreservation

Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.With increasing numbers of survivors of cancer in young people future fertility and ovarian function are important considerations that should be discussed before treatment commences. Some young people, by nature of the treatment they will receive, are at high risk of premature ovarian insufficiency and infertility. For them, ovarian tissue cryopreservation (OTC) is one approach to fertility preservation that remains both invasive and for young patients experimental. There are important ethical and consent issues that need to be explored and accepted before OTC can be considered established in children with cancer. In this review we have discussed a framework for patient selection which has been shown to be effective in identifying those patients at high risk of premature ovarian insufficiency (POI) and who can be offered OTC safely.PostprintPeer reviewe

Human ovarian reserve from conception to the menopause

Current understanding is that the human ovary contains a fixed number of several million non-growing follicles (NGF), established by five months of gestational age, that declines with increasing age to the menopause when approximately 1,000 NGF remain at an average age of 50-51 years. With approximately 450 ovulatory monthly cycles in the normal human reproductive lifespan, this progressive decline in NGF numbers is attributed to follicle death by apoptosis. Individual histological studies have quantified NGF numbers over limited age ranges. However, no model describing the rate of establishment and decline of the NGF population from conception to menopause has been previously reported. Here we describe the best fitting model of the age-related NGF population in the human ovary from conception to menopause. Our model matches the log-adjusted NGF population to a five-parameter asymmetric double Gaussian cumulative (ADC) curve (r2 = 0.81). Furthermore we found that the rate of NGF recruitment into growing follicles for all women increases from birth until approximately age 14 years (coinciding with puberty) then decreases towards the menopause. The explanation for this new finding remains unclear but is likely to involve both paracrine and endocrine factors. We describe and analyse the best fitting model for the establishment and decline of human NGF; our model extends our current understanding of human ovarian reserve

The effect of radiotherapy on the human reproductive system

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Family size and duration of fertility in female cancer survivors : a population based analysis

Funder: R.A.A. reports grant from Medical Research Council for the submitted work (Grant No. MR/N022556/1). T.W.K. has nothing to disclose. D.S.M. has nothing to disclose. W.H.B.W. has nothing to disclose.Objective: To assess family size and timescale for achieving pregnancy in women who remain fertile after cancer. Design: Population-based analysis. Setting: National databases. Patient(s): All women diagnosed with cancer before the age of 40 years in Scotland, 1981–2012 (n = 10,267) with no previous pregnancy; each was matched with 3 population controls. Intervention(s): None. Main Outcome Measure(s): The number and timing of pregnancy and live birth after cancer diagnosis, to 2018. Result(s): In 10,267 cancer survivors, the hazard ratio for a subsequent live birth was 0.56 (95% confidence interval, 0.53–0.58) overall. In women who achieved a subsequent pregnancy, age at live birth increased (mean ± SD, 31.2 ± 5.5 vs. 29.7 ± 6.1 in controls), and the family size was lower (2.0 ± 0.8 vs. 2.3 ± 1.1 live births). These findings were consistent across several diagnoses. The interval from diagnosis to last pregnancy was similar to that of controls (10.7 ± 6.4 vs. 10.9 ± 7.3 years) or significantly increased, for example, after breast cancer (6.2 ± 2.8 vs. 5.3 ± 3.3 years) and Hodgkin lymphoma (11.1 ± 5.1 vs. 10.1 ± 5.8 years). Conclusion(s): These data quantify the reduced chance of live birth after cancer. Women who subsequently conceived achieved a smaller family size than matched controls, but the period of time after cancer diagnosis across which pregnancies occurred was similar or, indeed, increased. Thus, we did not find evidence that women who were able to achieve a pregnancy after cancer had a shorter timescale over which they have pregnancies.Publisher PDFPeer reviewe

Perinatal germ cell development and differentiation in the male marmoset (Callithrix jacchus):similarities with the human and differences from the rat

STUDY QUESTION: Is perinatal germ cell (GC) differentiation in the marmoset similar to that in the human? SUMMARY ANSWER: In a process comparable with the human, marmoset GC differentiate rapidly after birth, losing OCT4 expression after 5–7 weeks of age during mini-puberty. WHAT IS KNOWN ALREADY: Most of our understanding about perinatal GC development derives from rodents, in which all gonocytes (undifferentiated GC) co-ordinately lose expression of the pluripotency factor OCT4 and stop proliferating in late gestation. Then after birth these differentiated GC migrate to the basal lamina and resume proliferation prior to the onset of spermatogenesis. In humans, fetal GC differentiation occurs gradually and asynchronously and OCT4(+) GC persist into perinatal life. Failure to switch off OCT4 in GC perinatally can lead to development of carcinoma in situ (CIS), the precursor of testicular germ cell cancer (TGCC), for which there is no animal model. Marmosets show similarities to the human, but systematic evaluation of perinatal GC development in this species is lacking. Similarity, especially for loss of OCT4 expression, would support use of the marmoset as a model for the human and for studying CIS origins. STUDY DESIGN, SIZE AND DURATION: Testis tissues were obtained from marmosets (n = 4–10 per age) at 12–17 weeks' gestation and post-natal weeks 0.5, 2.5, 5–7, 14 and 22 weeks, humans at 15–18 weeks' gestation (n = 5) and 4–5 weeks of age (n = 4) and rats at embryonic day 21.5 (e21.5) (n = 3) and post-natal days 4, 6 and 8 (n = 4 each). PARTICIPANTS/MATERIALS, SETTING AND METHODS: Testis sections from fetal and post-natal marmosets, humans and rats were collected and immunostained for OCT4 and VASA to identify undifferentiated and differentiated GC, respectively, and for Ki67, to identify proliferating GC. Stereological quantification of GC numbers, differentiation (% OCT4(+) GC) and proliferation were performed in perinatal marmosets and humans. Quantification of GC position within seminiferous cords was performed in marmosets, humans and rats. MAIN RESULTS AND ROLE OF CHANCE: The total GC number increased 17-fold from birth to 22 post-natal weeks in marmosets; OCT4(+) and VASA(+) GC proliferated equally in late gestation and early post-natal life. The percentage of OCT4(+) GC fell from 54% in late fetal life to <0.5% at 2.5 weeks of age and none were detected after 5–7 weeks in marmosets. In humans, the percentage of OCT4(+) GC also declined markedly during the equivalent period. In marmosets, GC had begun migrating to the base of seminiferous cords at ∼22 weeks of age, after the loss of GC OCT4 expression. LIMITATIONS, REASONS FOR CAUTION: There is considerable individual variation between marmosets. Although GC development in marmosets and humans was similar, there are differences with respect to proliferation during fetal life. The number of human samples was limited. WIDER IMPLICATIONS OF THE FINDINGS: The similarities in testicular GC differentiation between marmosets and humans during the perinatal period, and their differences from rodents, suggest that the marmoset may be a useful model for studying the origins of CIS, with relevance for the study of TGCC. STUDY FUNDING/COMPETING INTERESTS: This work was supported by Grant G33253 from the Medical Research Council, UK. No external funding was sought and there are no competing interests