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      The immature human ovary shows loss of abnormal follicles and increasing follicle developmental competence through childhood and adolescence

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          Abstract

          STUDY QUESTION

          Do the ovarian follicles of children and adolescents differ in their morphology and in vitro growth potential from those of adults?

          SUMMARY ANSWER

          Pre-pubertal ovaries contained a high proportion of morphologically abnormal non-growing follicles, and follicles showed reduced capacity for in vitro growth.

          WHAT IS KNOWN ALREADY

          The pre-pubertal ovary is known to contain follicles at the early growing stages. How this changes over childhood and through puberty is unknown, and there are no previous data on the in vitro growth potential of follicles from pre-pubertal and pubertal girls.

          STUDY DESIGN, SIZE, DURATION

          Ovarian biopsies from five pre-pubertal and seven pubertal girls and 19 adult women were analysed histologically, cultured in vitro for 6 days, with growing follicles then isolated and cultured for a further 6 days.

          PARTICIPANTS/MATERIALS, SETTING, METHODS

          Ovarian biopsies were obtained from girls undergoing ovarian tissue cryopreservation for fertility preservation, and compared with biopsies from adult women. Follicle stage and morphology were classified. After 6 days in culture, follicle growth initiation was assessed. The growth of isolated secondary follicles was assessed over a further 6 days, including analysis of oocyte growth.

          MAIN RESULTS AND THE ROLE OF CHANCE

          Pre-pubertal ovaries contained a high proportion of abnormal non-growing follicles (19.4 versus 4.85% in pubertal ovaries; 4004 follicles analysed; P = 0.02) characterized by indistinct germinal vesicle membrane and absent nucleolus. Follicles with this abnormal morphology were not seen in the adult ovary. During 6 days culture, follicle growth initiation was observed at all ages; in pre-pubertal samples there was very little development to secondary stages, while pubertal samples showed similar growth activation to that seen in adult tissue (pubertal group: P = 0.02 versus pre-pubertal, ns versus adult). Isolated secondary follicles were cultured for a further 6 days. Those from pre-pubertal ovary showed limited growth ( P < 0.05 versus both pubertal and adult follicles) and no change in oocyte diameter over that period. Follicles from pubertal ovaries showed increased growth; this was still reduced compared with follicles from adult women ( P < 0.05) but oocyte growth was proportionate to follicle size.

          LIMITATIONS, REASONS FOR CAUTION

          These data derive from only a small number of ovarian biopsies, although large numbers of follicles were analysed. It is unclear whether the differences between groups are related to puberty, or just age.

          WIDER IMPLICATIONS OF THE FINDINGS

          These findings show that follicles from girls of all ages can be induced to grow in vitro, which has important implications for some patients who are at high risk of malignant contamination of their ovarian tissue. The reduced growth of isolated follicles indicates that there are true intrafollicular differences in addition to potential differences in their local environment, and that there are maturational processes occurring in the ovary through childhood and adolescence, which involve the loss of abnormal follicles, and increasing follicle developmental competence.

          Study funding/competing interest(s)

          Funded by MRC grants G0901839 and G1100357. No competing interests.

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          Most cited references39

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          Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation.

          Aggressive chemotherapy/radiotherapy and bone marrow transplantation can cure >90% of girls and young women affected by disorders requiring such treatment. However, the ovaries are very sensitive to cytotoxic drugs, especially to alkylating agents. Several options are currently available to preserve fertility in cancer patients. The present review reports the results of 60 orthotopic reimplantations of cryopreserved ovarian tissue performed by three teams, as well as 24 live births reported in the literature to date. Restoration of ovarian activity occurred in almost all cases in the three series. Among the 60 patients, eleven conceived and six of those had already delivered twelve healthy babies. In the future, we are looking to: 1) improve freezing techniques; and 2) enhance the "vascular bed" before reimplantation to increase pregnancy rates. On the other hand, cryopreservation of ovarian tissue may be combined with removal, via puncture, of small antral follicles, making it possible to freeze both ovarian tissue and isolated immature oocytes. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
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            A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause

            Background Anti-Müllerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been previously reported. Methodology/Principal Findings By searching the published literature for AMH concentrations in healthy pre-menopausal females, and using our own data (combined ) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre-pubertal peak. Our model allows us to generate normative data at all ages. Conclusions/Significance These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman.
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              A two-step serum-free culture system supports development of human oocytes from primordial follicles in the presence of activin.

              The objective of this study was to determine whether follicles grown within human ovarian cortical strip culture for 6 days in serum-free medium could be isolated at the secondary stage of pre-antral development and grown in vitro to the late pre-antral/early antral stage during a 4 day culture period. Ovarian cortical biopsies were obtained from six women aged 26-40 years, with informed consent, during elective Caesarean section. Small tissue slices of ovarian cortex, with underlying stromal tissue removed, were cultured in serum-free medium for 6 days and at the end of this period pre-antral (secondary) follicles were dissected from the strips. Seventy-four intact pre-antral follicles ranging in size (66-132 microm) (mean size 100 microm +/- 3.4) were selected for further culture. Follicles were placed individually within V-shaped microwell culture plates in serum-free medium in the presence (n = 38) or absence (n = 36) of 100 ng/ml of human recombinant activin A. Pre-antral follicles grown for 4 days in the presence of activin A grew to a larger size (mean diameter 143 microm +/- 7.4) than those grown in control medium (mean diameter 111 microm +/- 8) (P 0.005). Of the follicles surviving the entire culture period, 30% of those cultured in the presence of activin A showed normal morphology with intact oocytes and antral formation. None of the follicles grown in control medium developed antral cavities and >90% of those follicles collected at the end of the culture period showed signs of oocyte degeneration. The results reported here demonstrate that under certain conditions, it is possible to achieve accelerated oocyte/follicle development from human primordial/primary follicles. This provides the first encouraging step towards achieving full in vitro growth of human oocytes.
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                Author and article information

                Journal
                Hum Reprod
                Hum. Reprod
                humrep
                humrep
                Human Reproduction (Oxford, England)
                Oxford University Press
                0268-1161
                1460-2350
                January 2014
                17 October 2013
                17 October 2013
                : 29
                : 1
                : 97-106
                Affiliations
                [1 ]MRC Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh , 47 Little France Crescent, Edinburgh EH16 4TJ, UK,
                [2 ]Centre for Integrative Physiology , University of Edinburgh , Hugh Robson Building, EdinburghEH8 9XD, UK,
                [3 ]Department of Paediatric Oncology, Royal Hospital for Sick Children , Edinburgh EH9 1LF, UK
                [4 ]Institute for Reproductive Health and Regenerative Medicine , Kansas University Medical Centre , Kansas City, KS 66085, USA
                Author notes
                [* ]Correspondence address. Tel: +44-131-2426386; E-mail: richard.anderson@ 123456ed.ac.uk
                Article
                det388
                10.1093/humrep/det388
                3860895
                24135076
                5c48862d-48d1-475e-a245-ae24b88c5ece
                © The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 July 2013
                : 27 August 2013
                : 25 September 2013
                Categories
                Original Articles
                Reproductive Biology

                Human biology
                ovary,adolescence,puberty,childhood,follicle
                Human biology
                ovary, adolescence, puberty, childhood, follicle

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