Academic Department of Obstetrics and Gynaecology, University of Aberdeen, UK
1 To whom correspondence should be addressed at: 15 Harriers Close, Ealing, London, W5 3UA, UK. e-mail: dnikolaou{at}talk21.com
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Abstract |
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Key words: IVF/ovarian ageing/screening
The basis of reproductive senescence in women is ovarian follicle depletion. The age-related decline of follicles in the human ovary is bi-exponential and more than doubles when numbers fall below a critical figure of 25 000 at 37.5 years of age (Faddy et al., 1992
). Brook et al. (1984
) reported that the early cessation of reproductive life in the mouse, brought on by unilateral oophorectomy, resulted in the early onset of irregular cyclicity and an increase in aneuploidy. Similar findings have been reported following oophorectomy in the human (Freeman et al., 2000
). Possibly the best follicles are recruited and selected first, at a younger age, leaving a greater proportion of poorer quality oocytes as the woman and her ovaries grow older.
Thus it has been suggested that a critical number of follicles rather than a critical age determines the time of the menopause (Faddy et al., 1992). The time needed to reach the menopause (1000 remaining follicles, average age 51 years) starting from the critical point of 25 000 follicles (average age 37.5 years) is stable at around 13 years. Likewise, the onset of subfertility prior to the menopause is likely to be at a fixed time, if only the time of the menopause could be predicted in an individual woman (Te Velde et al., 1998a
;b; Van Zonneveld et al., 2001
; Te Velde and Pearson, 2002
). Also the same, mainly genetic factors that determine the age of the menopause, will also determine the age of all reproductive milestones that precede the menopause, including onset of subfertility.
Richardson et al. (1987) reported that the number of primordial follicles in the ovaries of regularly menstruating women was 10-fold higher than in women with irregular periods. Den Tonkelaar et al. (1998
) found that the time interval between the loss of menstrual regularity and the menopause was
6 years, regardless of age at menopause. However the time of onset of subfertility, for individual women, is more difficult to ascertain. Data from assisted reproduction studies have provided indirect evidence that the time-interval between the onset of accelerated decline in fertility and the menopause must also be fixed. Women who respond poorly to ovarian stimulation with gonadotrophins, become menopausal earlier (Farhi et al., 1997
; Crosignani et al., 2000
; De Boer et al., 2002
; Nikolaou et al., 2002
; Lawson et al., 2003
) and in this respect IVF can be viewed as a dynamic test of ovarian reserve (Beckers et al., 2002
). It has been suggested that the size of the cohort of follicles >2 mm, likely to respond to exogenous gonadotrophin stimulation during IVF, may be a reflection of the actual resting follicle pool (Gougeon, 1996
; Scheffer et al., 1999
). Poor response to ovarian stimulation most likely represents a stage between onset of accelerated decline and total loss of fertility, whereas non-response corresponds to a total loss of fertility.
Assuming an interval of 13 years between the age of accelerated decline of fertility (25 000 follicles) and the menopause, it can be speculated that women who become menopausal by the age of 45 will have begun to experience an accelerated decline in fertility around the age of 32 years (25 000 remaining follicles). Nevertheless, they may continue to be otherwise asymptomatic, with regular menstrual cycles, for several more years. These women should perhaps be classified as a new clinical entity,early ovarian ageing. Because of the long latent phase, this condition may be suitable for screening in the general population, starting in the early thirties. Epidemiological studies have shown that 10% of women in the general population become menopausal by the age of 45 (Treloar, 1981; van Noord et al., 1997
), and it is therefore estimated that 10% of women in the general population might be at risk. These women could have reduced fecundity which is otherwise unexplained (Scott et al., 1993
; Hofmann et al., 1996
; Leach et al., 1997
). They could experience increased incidence of dizygotic twinning (Wyshak, 1975
; Turner et al., 1994
; Martin et al., 1997
; Lambalk et al., 1998
), increased incidence of aneuploidy (Nasseri et al., 1999
; van Montfrans et al., 1999
; Freeman et al., 2000
; van Montfrans et al., 2002
) and miscarriage (Trout and Seifer, 2000
). They will also have a relatively poor response to ovarian stimulation. Assuming fixed time-differences between reproductive milestones, fertility will not be lost completely for 4 years, on average, following diagnosis. Menstrual cycles will continue to be regular, although relatively short, for 68 more years on average (Den Tonkelaar et al., 1998
). Furthermore, these women might exhibit other physical and possibly mental and psychological signs compatible with accelerated general ageing (Dorland et al., 1998
).
Screening for early ovarian ageing would probably be more effective in high-risk groups. Assuming that the same, mainly genetic, factors, which affect the time of menopause (Cramer et al., 1995; van Noord et al., 1997
; Torgerson et al., 1997a
; b; Snieder et al., 1998
; Treloar et al., 1998
; De Bruin et al., 2001
; Te Velde and Pearson, 2002
) will also determine all preceding reproductive milestones, a high-risk group for early ovarian ageing would include women with a family history of an early menopause. Other possible acquired factors may include: chemotherapy, radiotherapy, pelvic surgery (Lass et al., 1998
; Tulandi et al., 2002
), pelvic infections or tubal disease (Keay et al., 1998
; Sharara, 1998
), severe endometriosis (Barnhart et al., 2002
), and heavy smoking (Augood et al., 1998
). With regards to primary prevention, smoking, pelvic infection and surgical interventions may be avoidable. Screening for early ovarian ageing in the early thirties could provide information to women, on which to base rational decisions about their fertility without risking involuntary childlessness. In the longer term advances in molecular reproductive biology and pharmacology may enable us to develop drugs or interventions that will delay the accelerated decline of ovarian reserve in some women.
An important contribution of assisted reproduction has been the development of tests for the assessment of the ovarian reserve. Among the tests already in use are basal biochemical markers, dynamic assays, biophysical tests, and ovarian biopsies. The driving force for the initial development of these tests was the desire to predict IVF outcome. However, some of them might be suitable as screening tools for early ovarian ageing in the general population. Small antral follicular counts (Broekmans et al., 1998; Bancsi et al., 2002
) and new biochemical markers, such as antimüllerian hormone (De Vet et al., 2002
), appear promising and warrant further evaluation. Ultimately, with developments in molecular genetics, it might become possible to construct DNA fingerprints that will identify women with a genetic predisposition to early ovarian ageing (Te Velde and Pearson, 2002
).
In conclusion, on the basis of a fixed interval of 13 years between onset of accelerated decline of fertility (25 000 remaining follicles) and the menopause, it can be speculated that women who become menopausal by the age of 45 years, have experienced an accelerated decline of fertility around the age of 32. These women can be classified under a separate clinical entity, early ovarian ageing, which possibly affects 10% of the general population, and is potentially suitable for screening. IVF provides a model for the development of ovarian reserve tests; some of which could eventually enable us to detect early ovarian ageing in asymptomatic young women in the general population.
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References |
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