Reproductive toxicity of cyclophosphamide in the C57BL/6N mouse: 1. Effects on ovarian structure and function
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Antral follicle
Recent scientific research into pre-antral follicular dynamics has resulted in the discovery of a wide range of hormones and local factors that influence primordial follicle activation and contribute to follicular development. The putative role of several of these mediators in the follicle growth process has been elucidated by genetic and molecular investigations. Crucial questions, such as the mechanism for primordial follicle initiation and the interplay between oocyte and granulosa cells in this process, remain however unresolved. This review article commences with a description of the embryogenesis of the ovary and follicles. Next, the different stages in the development from primordial to pre-antral follicle are discussed. Thereafter, a short overview of the various in vitro models for the study of follicular dynamics is presented. Finally, an in-depth discussion of pre-antral follicle development engages in the current hypotheses regarding primordial follicle activation, and the role of gonadotrophins and angiogenesis.
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Abstract Serum anti-Müllerian hormone (AMH) is a biomarker for predicting antral follicle counts but there is no clear consensus on whether AMH is indicative of primordial follicle counts in humans. Mice were used as a model species in this study to obtain accurate follicle counts across the reproductive phase of life. Serum AMH was measured in 62 female C57Bl6/J mice aged 25 to 401 days. Primordial and primary follicles were determined by stereological counts and all secondary and antral follicles were counted in serial histological sections. Serum AMH was most strongly correlated with small- and medium-sized antral follicles. Immunohistochemistry and stepwise multiple regression confirmed that these follicle development stages are the key determinants of serum AMH, with little contribution from other stages. Primordial follicles were not found to have strong correlations with serum AMH or antral follicle counts, particularly in younger females, but the strength of the association appeared to increase with age. This result is likely attributed to high interindividual variation in primordial follicle activation and preantral follicle survival rates. Recent large studies in human populations have shown similar results but the primary limitation of these studies was that primordial follicle counts were determined from ovarian cortical biopsies, where regional variation in follicle distribution may affect the quality of the data. In the present study, whole ovaries were surveyed, eliminating this limitation. The findings indicate that primordial follicle counts are not closely related with either serum AMH or antral follicle counts in females in the early phase of the reproductive phase of life.
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The ability of an oocyte to successfully mature is highly dependent on intrafollicular conditions, including the size and structure of the follicle. Here we present a mathematical model of oxygen transport in the antral follicle. We relate mean oxygen concentration in follicular fluid of bovine follicles to the concentration in the immediate vicinity of the cumulus‐oocyte complex (COC). The model predicts that the oxygen levels within the antral follicle are dependent on the size and structure of the follicle and that the mean level of dissolved oxygen in follicular fluid does not necessarily correspond to that reaching the COC.
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The assembly of the developmentally arrested primordial follicle and the subsequent transition of the primordial follicle to the primary follicle are critical processes in normal ovarian physiology that remain to be elucidated. Ovarian follicles do not proliferate and the primordial follicles present in the neonate represent the total number of gametes available to a female throughout her reproductive life. The primordial follicles are oocytes surrounded by less differentiated squamous granulosa cells and are derived from oocyte nests, and primary follicles are oocytes surrounded by a single layer of cuboidal granulosa cells that have initiated follicle development. Abnormalities in primordial follicle assembly, arrest, and development (i.e. primordial to primary follicle transition) can cause pathological conditions such as premature ovarian failure. In this study newborn rat ovaries were cultured for 7 d. The rate of primordial follicle assembly in vivo was identical with the rate in vitro. Interestingly, the rate of primordial follicle transition to the primary follicle was found to be 3 times greater in culture. This abnormal rate of primary follicle development in culture suggests the primordial follicle does not arrest in development as observed in vivo. To investigate this phenomena newborn rat ovaries were cultured in the presence of progesterone, estradiol or calf serum. Estradiol, progesterone, or calf serum significantly reduced the level of initial primordial to primary follicle transition. Approximately 60% of follicles make the primordial to primary follicle transition in control ovaries and about 30% in treated ovaries. Steroids and calf serum had no effect on the primordial to primary follicle transition in ovaries collected and cultured from postnatal 4-d-old rats, suggesting the effects observed are restricted to the initial wave of primordial to primary follicle transition. Interestingly, progesterone was also found to significantly reduce the rate of primordial follicle assembly. All viable oocytes assembled into primordial follicles in control ovaries and approximately 40% remained unassembled in progesterone-treated ovaries. Progesterone was also found to reduce primordial follicle assembly in vivo with 10% of the total follicles remaining unassembled in progesterone injected neonatal animals. Analysis of cellular apoptosis demonstrated that progesterone inhibited the coordinated oocyte apoptosis required for primordial follicle assembly. The hypothesis developed is that high levels of maternal and fetal steroids prevent premature primordial follicle assembly and primordial to primary follicle transition in the embryo. After birth steroid levels fall dramatically and the primordial follicles are free to assemble and initiate development. These observations suggest a novel role for steroids and the maternal-fetal endocrine unit in the control of ovarian primordial follicle assembly and early follicular development.
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This study was designed to describe, both quantitatively (morphometry) and qualitatively (histological differentiation), follicle and oocyte growth in the feline ovary. The ovaries of 43 cats were collected and processed for histology. The diameters of 832 follicle/oocyte pairs were measured, with and without zona pellucida (ZP), and a special emphasis was placed on the study of early folliculogenesis. Primordial, primary, secondary, pre-antral and early antral follicles were measured at 44.3, 86.2, 126.0, 155.6 and 223.8 microm in diameter respectively. A biphasic pattern of follicle and oocyte growth was observed. Before antrum formation, follicle (x) and oocyte (y) size were positively and linearly correlated (y = 0.500x + 20.01, r(2) = 0.89). Antrum formation occurred when the follicle reached 160-200 microm in diameter (when oocyte was at 102 microm). After antrum formation, a decoupling was observed, a minimal increase in oocyte size contrasting with a significant follicle development (y = 0.001x + 114.39, r(2) = 0.01). The pre-ovulatory follicle diameter was approximately 3500 microm and the maximal oocyte diameter was 115 microm. The ZP, absent in primordial and primary follicles, appeared at the secondary stage and reached almost 6 microm at the pre-ovulatory stage. These results suggest that (i) in feline ovary, follicle and oocyte growth pattern is similar to that observed in other mammals; (ii) the antrum forms in 160-200 microm follicles, which represents 5% of the pre-ovulatory diameter and (iii) the oocyte had achieved more than 90% of its maximal growth at the stage of antrum formation.
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Summary. Follicular growth was stimulated by the administration of PMSG to immature female hamsters. Changes in the number and size of follicles, their content of progesterone, testosterone, oestradiol, and oestrone (determined in whole follicular homogenates) and the meiotic status of the oocytes, were followed for 4 days to monitor follicular development and ageing. The results showed that 92% of small antral follicles (371–590 μm) were seen 24–30 h after PMSG stimulation and that the maximum number of medium- (591–740 μm) and large- (>740 μm) sized antral follicles occurred >48 h later. There was a progressive increase in the concentrations of testosterone, oestradiol and oestrone over the first 48–54 h, but maximal values of oestrone (geometric mean (limits of 1 s.d.): 326·5 (230·4–462·7) pg/follicle) lagged 24 h behind the highest values for testosterone (352·5 (242·0–456·0) pg/follicle) and oestradiol (718·4 (315·7–1634·7) pg/follicle). The progesterone content of all follicles did not change significantly during the first 72–78 h (range of geometric mean values: 0·25–1·06 ng/follicle), but at 96–102 h two populations of mediumand large-sized follicles could be distinguished on the basis of a low progesterone concentration (Group 5a: medium, 0·27 (0·13–0·55) ng/follicle; large, 0·1 (0·08–0·13 ng/follicle; P < 0·01) or a high concentration (Group 5b: medium, 7·77 (3·12–19·36) ng/follicle: large, 13·10 (8·68–19·76 ng/follicle; P < 0·01) and this grouping corresponded to the peripheral plasma progesterone values of the animals (Group 5a: 1·32 (0·51–3·42) ng/ml; Group 5b: 6·76 (5·05–9·05) ng/ml; P < 0·01). Differences in concentrations of testosterone, oestradiol and oestrone were not found in these two groupings at 96–102 h, but large antral follicles at this time contained more oestrone (x 1·5) than medium-sized follicles. Oocytes recovered from follicles up to 78 h after PMSG stimulation showed few signs of atresia (>80% viable) and had not resumed meiosis (>93% had a visible germinal vesicle). At 96–102 h oocytes from medium and large follicles with a low progesterone content maintained their viability (>88%), but 41% of oocytes recovered from medium-sized follicles showed evidence of germinal vesicle breakdown. However, in follicles containing high concentrations of progesterone the incidence of atresia was high (38–48%) and most oocytes had resumed meiosis (>97%).
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Antral follicle size might be a valuable additive predictive marker for IVF outcome. However, while some studies show positive relations between follicle size and reproductive outcome, others have not been successful in establishing this relation. To better understand consequences of antral follicle size for reproductive outcome, we aimed to obtain insight in follicle size-related granulosa cell processes, as granulosa cells play an essential role in follicular development via the production of growth factors, steroids and metabolic intermediates, needed for follicular growth and oocyte development. Using pigs as a model, we compared gene and protein expression in granulosa cells of smaller and larger follicles in the healthy antral follicle pool at the start of the follicular phase of the estrous cycle. In sows, the early antral follicle pool is very heterogeneous when e.g. size and steroid content of the follicular fluid are considered. To which extent this variety contributes to the developmental competence of the follicles is not clear. Therefore, sows with high variation in antral follicle size (HighVAR) as well as sows with low variation in antral follicle size (LowVAR) were used. Granulosa cells of smaller antral follicles in the healthy antral follicle pool show increased cell proliferation, which was accompanied by a metabolic shift towards aerobic glycolysis (i.e. the Warburg effect), similar to other highly proliferating cells. High granulosa cell proliferation rates in smaller follicles might be regulated via increased granulosa cell expression of AR and EGFR which are activated in response to locally produced mitogens. While granulosa cells of smaller follicles in the pool were more proliferative, indicative of higher follicular growth, granulosa cells of larger follicles in the pool showed less proliferation and were more differentiated, as they showed a higher expression of follicular maturation marker IGF1 and ANGPT1. Our results imply that the inclusion of strict criteria of antral follicle size in IVF protocols might improve reproductive outcome. In addition, we have granulosa cell gene expression of healthy follicles to unravel underlying mechanisms of differences in COC morphology. We compared gene expression in sows with low vs. high-COC-health and found a decreased expression of genes involved in ovarian steroidogenesis (e.g. CYP19A1, ADM, SPP1) and higher expression of genes involved in follicular atresia (e.g. GADD45A, INHBB) in sows with low-COC-health. Thereby we have identified several genes which may serve as markers for follicle developmental competence.
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Follicle development requires complex and coordinated interactions between both the oocyte and its associated somatic cells. In ovarian dysfunction, follicle development may be abnormal due to defective somatic cell function; for example, premature ovarian insufficiency or malignancies. Replacing defective somatic cells, using the reaggregated ovary (RO) technique, may 'rescue' follicle development. ROs containing mature follicles have been generated when transplanted to a host mouse to develop. We have developed a RO culture technique and the aims were to determine how follicle development differed between transplanted and cultured ROs, and the influence of ovarian age (P2 vs P6). Mouse ROs were cultured for 14 days; P2 and P6 ovaries cultured as Controls. Follicle development was compared to ROs transplanted for 14 days and ovaries from P16 and P20 mice. ROs generated from either P2 or P6 exhibited similar follicle development in culture whereas in vivo follicle development was more advanced in P6 ROs. Follicles were more developed in cultured ROs than transplanted ROs. However, follicles in cultured ROs and ovaries had smaller oocytes with fewer theca and granulosa cells than in vivo counterparts. Our results demonstrate the fluidity of follicle development despite ovary dissociation and that environment is more important to basal lamina formation and theca cell development. Furthermore, follicle development within cultured ROs appears to be independent of oocyte nest breakdown and primordial follicle formation in source ovaries. Our results highlight the need for understanding follicle development in vitro, particularly in the development of the RO technique as a potential fertility treatment.
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