Assisted Conception Unit, Chelsea and Westminster Hospital, Imperial College, London, UK
1 To whom correspondence should be addressed at: Assisted Conception Unit, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Email: dnikolaou{at}talk21.com
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Abstract |
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Key words: early ovarian ageing/fetal origin/IVF/IVM/PCOS/polycystic ovaries
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Introduction |
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Ovarian reserve tests and PCO |
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Oocyte quality in early ovarian ageing and what happens in PCO |
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Although women with PCO tend to develop many follicles in response to ovarian stimulation, initial data from IVF programmes reported that their fertilization rates tended to be relatively low (Homburg et al., 1993; Buyalos and Lee, 1996
). The interpretation of these initial observations would be that, in PCO, there is compromised oocyte quality, despite the large number of follicles. Women with PCO were also thought to have a tendency to higher miscarriage rates, following both natural and assisted conception (Balen et al., 1993a
, b
) and had a higher incidence of recurrent miscarriage (Sagle et al., 1988
). More recent data, however, have shown that all these statements are true only in cases of polycystic ovary syndrome (PCOS), i.e. menstrual irregularity and hyperandrogenism associated with polycystic ovary morphology on ultrasound (Franks, 1995
; Rotterdam consensus, 2004
). Current thinking is that most of the long-term reproductive disruptions and general health problems associated with PCOS are related to the degree of hyperisulinaemia and insulin resistance (Elting et al., 2001a
). The hypersecretion of LH in PCOS is probably related to impaired negative feedback on LH secretion. Clinical studies involving women with PCO on ultrasound, but no clinical manifestations of the PCOS, have shown more oocytes, more embryos and much higher cumulative pregnancy rates in women with PCO. The miscarriage rates were similar (not higher) to women with normal ovaries, which would suggest comparable oocyte quality (Engman et al., 1999b
; Nikolaou et al., 2002b
). In a recent casecontrol study aiming to evaluate the effect on fertility of the appearance of PCO in women who had no symptoms of PCOS (Hassan and Killick, 2003
), the time to pregnancy of women with PCO, but no symptoms, was not significantly longer and they were not more likely to be subfertile than women with normal ovaries. It has also been shown that asymptomatic women with PCO (no clinical PCOS) do not have higher rates of recurrent miscarriage (Rai et al., 2000
). Thus, women with PCO, but no clinical PCOS, seem to have not only a larger number, but also good quality, oocytes. In women with PCOS, the reproductive disruptions seem to be caused by abnormal final follicle maturation in vivo (Fauser, 1994
). This seems to be partly improved in in vitro maturation programs, where patients with PCOS tend to have significantly more oocytes collected and higher fertilization, cleavage and pregnancy rates than women with normal ovaries (Child et al., 2001
; Tan et al., 2002
). In these studies the number of antral follicles at a baseline scan was more important in predicting outcome as compared to whether morphology was polycystic or normal.
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Origin of the increased antral follicle cohort in PCO |
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Morphometric studies in the human (Gougeon et al., 1994; Gougeon, 1996
) have shown that, generally, there is a good correlation between the cohort of growing antral follicles and the pool of resting and small pre-antral follicles. A crucial question is whether the same is true for PCO. Hughesdon (1982)
had compared sampled sections from archived normal and PCO and found that there were similar numbers of primordial follicles, but the latter had twice as many growing and atretic follicles. In an important recent study, it was reported that the median density of small follicles, including those at primordial and primary stages, was 6-fold greater in anovulatory PCO than in normal ovaries (Webber et al., 2003
). The primordial follicle density again did not differ between women with normal and PCO, but the difference in density of primary follicles was significant. Although the studies were done on adult ovaries, the high density of primary follicles in PCO supports the notion that these women may have actually been be born with a larger ovarian reserve (Webber et al., 2003
). This would be in agreement with the hypothesis that the rate of decline of the ovarian reserve depends on the size of the pool of remaining follicles (Faddy et al., 1992
; Gougeon, 1996
). An alternative explanation for the same density of primordial, but higher density of primary follicles in PCO, reported in both studies, could be that there is an over-recruitment of follicles into the growing stages. The result would have been accelerated ovarian ageing. This is not actually supported by data on long-term follow-up of women with PCO, which do not show any evidence of an early menopause in these women (Dahlgren et al., 1992
; Elting et al., 2000
; Amer et al., 2002
). A third possibility, of course, is that the larger pool of early growing follicles in PCO is only due to a slower progression through the later stages of follicle development (Mason, 2000
; Webber et al., 2003
; Jonard and Dewailly, 2004
). There is mounting evidence that all the above are actually true. Women with PCO are probably born with a larger pool of resting follicles (Webber et al., 2003
). Initially, there is accelerated entry to the early growing stages, and thereafter a relatively slow growth through the pre-antral stages (Webber et al., 2003
; Jonard and Dewailly, 2004
). This slow growth may be a result of the large size of the small-follicle pool. It is known that, in general, most oocytes are lost with attrition in fetal life. The main mechanism of reduction of the reserve of resting follicles in late reproductive year appears to be through accelerated entry to the late growing phase, when apoptosis is mainly located in the granulosa cells (Gougeon, 1996
; Vaskivuo et al., 2001
; de Bruin et al., 2004
). On this basis it can be speculated that, in cases of early ovarian ageing, the waves of follicles entering the antral stage must be more frequent. On the contrary, in women with PCO, where the initial pool of resting follicles is relatively large and the size of the cohort of growing follicles is correspondingly large, it is likely that the frequency of the waves of follicles entering the antral stage will be slower.
It is plausible that, in terms of evolution, increasing the size of the ovarian reserve at birth has been nature's way to adjust the ovarian biological clock, in order to preserve fertility in the face of an adverse environment. In agreement with the predictions of the fetal origin hypothesis, this trait can become potentially detrimental in different conditions (Prentice, 2003), when the PCOS develops. The age of menopause has high inheritability (te Velde and Pearson, 2002
) and the same is probably true for all reproductive milestones that precede the menopause and depend on the number of remaining follicles (te Velde et al., 1998a
, b
). Likewise, there is plenty of evidence for a genetic basis of PCOS although the genes that contribute are still uncertain (Franks, 2002
). Although the literature on this point remains controversial (Cresswell et al., 1997
; Ibanez et al., 1998
, 1999
; Sadrzadeh et al., 2003
), it is possible that, in fetuses that are genetically predisposed to having a large pool of resting follicles at birth (and PCO after puberty), a certain environment at a critical window of fetal development, such as maternal hyperandrogenaemia, hyperinsulinaemia, or stress, can cause fetal hyperandrogenaemia. This programs the hypothalamopituitaryadrenal axis towards preferential abdominal adiposity later on in life, which predisposes to insulin resistance and PCOS (Abbott et al., 2002
; Eisner et al., 2002
). Whether this syndrome will actually develop or not, and to what extent, will depend on the degree of hyperandrogenaemia, as well as other genetic and environmental factors acting after puberty, mainly obesity. Those women who have more follicles (hormone-producing) will be more prone to excessive ovarian androgen production in response to certain environmental stimuli. In fact, the cohort of antral follicles, like the number of small preantral follicles, is larger in women with PCOS than asymptomatic women with PCO (Elting et al., 2001b
; Webber et al., 2003
). The symptoms of the PCOS tend to regress or disappear when some of the follicles are lost, either in older age or following surgical intervention (Elting et al., 2000
, Elting et al., 2003
; Amer et al., 2002
).
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Conclusion |
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References |
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Submitted on January 5, 2004; resubmitted on April 13, 2004; accepted on June 24, 2004.
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