1 Department of Public Health, Bexley PCT, Bexleyheath DA7 6HZ, 2 Assisted Conception Unit, Guys Hospital, London SE1 9RT, 3 Assisted Conception Unit, Kings College Hospital, London SE5 9RS and 4 Maternal and Fetal Research Unit, St Thomas Hospital, London SE1 7EH, UK
5 To whom correspondence should be addressed at: Assisted Conception Unit, 4th Floor, Thomas Guy House, Guys Hospital, St Thomas Street, London SE1 9RT, UK. e-mail: tarekeltoukhy{at}hotmail.com
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Abstract |
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Key words: early menopause/IVF/ovarian reserve/poor ovarian response
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Introduction |
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The prevailing hypothesis on the aetiology of the menopause is exhaustion of the follicle pool in the ovaries (Blocke, 1952; Baker, 1963
). The overwhelming majority of oocytes are lost by atresia, a process that begins in early gestation and continues until a few years following menopause (Costoff and Mahesh, 1975
). The number of oocytes decreases particularly rapidly in the years immediately preceding the menopause (Richardson et al., 1987
; Faddy et al., 1992
; Gougeon et al., 1994
). This reduction in oocyte numbers in the peri-menopause (so-called reduced ovarian reserve) is accompanied by a rise in serum follicular phase FSH levels (Sherman et al., 1976
; Ebbiary et al., 1994
). However, basal FSH levels can be highly variable in the peri-menopausal period (Martin et al., 1996
) and the value of a single raised FSH level in predicting the onset of menopause is unclear.
Within the UK, 27 151 women underwent 33 884 cycles of assisted reproduction treatment in 19981999 (Human Fertilisation and Embryology Authority, 2000). The administration of gonadotrophins to such women has highlighted an important group who fail to respond to ovulation induction therapy with appropriate follicular development, despite having normal basal FSH levels (<10 IU/l). It has been suggested that this poor response to ovulation induction may be an early sign of impaired ovarian reserve, preceding the peri-menopausal rise in FSH (Tanbo et al., 1992; Farhi et al., 1997
).
We sought to determine whether poor response to ovulation induction or elevated basal serum FSH (>10 IU/l) in women aged <40 years who underwent assisted reproduction treatment can be used as predictors of early menopause and poor fertility outcome.
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Materials and methods |
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Patients
From a database of 6000 patients treated between 1987 and 1998, three groups were identified.
Group 1 (poor responders)
Women who had a normal basal FSH level (<10 IU/l) and exhibited a poor response to ovulation induction. Poor response was defined as stimulation with our maximum dose of 450 IU of gonadotrophins daily for a minimum of 9 days and either: (i) <4 oocytes obtained at oocyte retrieval, or (ii) cycle cancellation prior to oocyte retrieval because of poor follicular development (<3 follicles of 14 mm after 912 days of stimulation).
Group 2 (raised FSH)
Women who exhibited an elevated basal FSH level (10 IU/l) during the course of their IVF/ICSI treatment and therefore were stimulated with a similar gonadotrophin dose of 450 IU daily.
Group 3 (controls)
A control group composed of women of the same age group who had a normal basal FSH level (<10 IU/l), underwent IVF/ICSI during the same time period, and from whom 6 oocytes were obtained at oocyte collection following stimulation with a daily gonadotrophin dose appropriate for their age (150 IU if 2530 years, 225 IU if 3135 years or 300 IU if 3639 years).
Procedure
All women were sent a postal questionnaire and a study information letter signed by the treating consultant in 20002001 seeking information regarding current menstrual function (i.e. cycle length and regularity), vasomotor symptoms, past medical and surgical history, hormonal drug treatment, subsequent assisted reproduction treatment and spontaneous pregnancies, and pregnancy outcome. For those with menstrual dysfunction and/or vasomotor symptoms, the date of onset of symptoms was recorded. Those who had undergone uterine and/or ovarian surgery, or who had commenced the oral contraceptive pill or a GnRH analogue or had chemotherapy or radiotherapy for any reason during the follow-up period were excluded from follow-up at the time of surgery or beginning of drug therapy.
The general practitioners of all women who did not reply to the first questionnaire were contacted to confirm the patients address. Questionnaires were sent up to three times to a womans last known address. Data with respect to gynaecological history, previous pregnancies, cause and duration of infertility, all IVF/ICSI treatment prior to and subsequent to inclusion in the study were obtained from the medical files of patients who returned the questionnaire.
Outcome measures
The main outcome measures were ovarian function, pregnancy rates and pregnancy outcome. Ovarian function was assessed by recording the occurrence of the menopause and/or symptoms of the peri-menopause. Menopause was defined as amenorrhoea for 12 months (excluding pregnancy and lactation) and/or continuous use of hormone replacement therapy (HRT) for >6 months duration prior to completion of the questionnaire. Peri-menopause was defined as the presence of menstrual cycle change [either short (<21 days) or long (>35 days) in women who previously had a regular 2535 day cycle], and/or vasomotor symptoms (hot flushes or night sweats at a frequency of >1 episode/day). Pregnancy rates and pregnancy outcome were recorded for pregnancies which arose as a result of assisted reproduction treatment, and which occurred spontaneously following cessation of treatment. Pregnancies arising from ovum/embryo donation were excluded from the analysis
Power calculation and statistical analysis
After identifying all cases in groups 1 and 2 (n = 261 and 258 respectively), a pilot study was undertaken which gave a 50% response rate. Given that the prevalence of early menopause is 1% and with a response rate of 50%, it was calculated that a control group twice as large as each of the two study groups would be required to give the study a power of 90% to detect a 10-fold increase in the risk of early menopause with a P-value of 0.05. Data analysis was undertaken using Stata version 5.0 for Windows (Stata Corporation, TX, USA). Baseline characteristics were compared using one-way analysis of variance for means and
2-test for proportions. Ovarian function was compared using KaplanMeier life table (survival) analysis. Adjustment was made for age at the time of treatment and smoking habits using logistic regression analysis. A hazard ratio (i.e. relative risk estimate), 95% confidence intervals (CI) and significance tests were calculated using the Cox regressionBreslow method for ties. Assisted reproduction treatment and spontaneous pregnancy rates were compared using a
2-test.
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Results |
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Baseline characteristics of the three groups of women at the time of treatment were compared (Table I). The mean age of the whole study population at the time of treatment was 34 years. There was a small but statistically significant difference in the mean age between the three groups. Women with poor response and those with raised FSH were on average 12 years older than those in the control group (35.6, 34.7 and 33.1 years respectively, P = 0.01). However, there was no significant difference between the three groups with respect to the proportion of women who had a previous pregnancy or mean duration and cause of infertility. Equal proportions of each group received their treatment before or during 1994.
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Poor responders produced the least number of oocytes when compared with the other two groups (P < 0.0001). The mean number of retrieved oocytes was also significantly lower for women with raised FSH compared with controls (P < 0.001).
Ovarian function
The follow-up period in the study ranged between 2.8 and 12.7 years (mean 5.6 ± 2.1 years) and the mean follow-up period was similar in the three study groups. During follow-up, 46 women with poor response (39%), 49 with raised basal FSH level (30%) and 41 controls (16%) have developed peri-menopausal symptoms. The corresponding numbers for those who developed the menopause were 13 (11%), 3 (2%) and 1(0.38%) respectively.
After adjustment for age and smoking habits, KaplanMeier life table analysis (Figures 1 and 2) showed that both women with poor response (group 1) and raised FSH (group 2) were more than twice as likely as controls to develop symptoms of the peri-menopause within 10 years of receiving IVF treatment (hazard ratio 2.40 and 2.76 respectively, P < 0.0001) (Table II, Figure 1). Moreover, women who exhibited a poor response to ovulation induction were 23 times more likely to become menopausal within 10 years of IVF treatment than controls and nearly six times more likely to reach the menopause within 10 years of treatment than those with a raised basal FSH level (hazard ratio 23.9 and 5.97, P = 0.002 and 0.015 respectively). Women with raised FSH were also more likely to become menopausal during the period of follow-up than controls, although this difference did not reach statistical significance (hazard ratio 9.25, P = 0.06) (Table III, Figure 2).
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Pregnancy outcome
The total numbers of pregnancies (assisted reproductive treatment and spontaneous) achieved by women with poor response, raised FSH and controls were 33, 59 and 197 respectively. Table V summarizes the outcome of these pregnancies. The lowest live birth rate (66.7%) and highest miscarriage rate (33.3%) were seen in women with poor response. The highest live birth rate (75.1%) and lowest miscarriage rate (21.3%) were seen in controls. However, due to small numbers, these differences did not reach statistical significance.
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Discussion |
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There are two potential sources of bias in the study. First, the overall response rate to the questionnaire was lower in women with poor response than in women with raised basal FSH (45 and 64% respectively, P = 0.01). This study required participation of patients who had left treatment for many years. Thus there was difficulty in obtaining the current address for each woman as it is possible that some have moved since treatment.
Self-selection was another potential source of bias. This may act in two main ways. First, it is possible that women whose treatment was unsuccessful might be less likely to reply to the questionnaire than those who became pregnant with treatment. This would apply more to women with poor response, as their assisted reproductive treatment pregnancy rates were lowest. Second, it is possible that women who became menopausal or developed peri-menopausal symptoms following treatment were more likely to reply to the questionnaire than those who remained symptom-free.
We tested the effect of selection bias on our hypothesis by assuming that all women who did not reply to the questionnaire had normal menstrual cycle and were symptom-free when sent the questionnaire. We then included these women in a 2-test of the difference in incidence of menopause and/or peri-menopause, comparing first poor responders and controls, and then women with raised FSH and controls. The difference in incidence of menopause and/or peri-menopausal symptoms remained statistically significant (P = 0.001 and 0.01 respectively), indicating that selection bias does not invalidate the findings of our study.
Thus, this study supports the hypothesis that poor response and raised basal FSH level are markers of reduced ovarian reserve and predictive of early onset of menopause. Our findings corroborate those of De Boer et al. (2002), who used data from a nationwide Dutch study to estimate the risk of early menopause in poor responders to IVF stimulation and demonstrated that their relative risk is 811 times that of normal responders. Nikolaou et al. (2002
) reported a retrospective study of 12 young non-responders and demonstrated a strong association between lack of response to ovulation induction and early ovarian failure. Although the latter two studies also used normal responders as a control group, unlike our study, they did not report data on pre-treatment basal FSH levels.
Our study also highlights that women who exhibit a poor response to ovarian stimulation and those who had a raised basal FSH level are more likely to suffer climacteric symptoms earlier than controls. Climacteric symptoms can influence daily activities and interfere with physical and psychological comfort. Moreover, these symptoms might be more distressing in younger infertile women (Bryson et al., 2000; Liao et al., 2000
; Bloche, 2002
). Therefore, sufficient medical attention and appropriate counselling should be made available for these women to limit the adverse effects of such symptoms, particularly in light of recent research suggesting that it is the climacteric symptoms, not the menopausal status, that are associated with higher rates of depressive symptoms at midlife (Bosworth et al., 2001
).
Counselling may also be important with regard to the chances of spontaneous conception following failed assisted reproductive treatment and discontinuation of treatment. Our results show that 10% of poor responders and women with a raised basal FSH level will conceive spontaneously within 212 years. This proportion is similar to those reported in previous series involving follow-up of couples after assisted reproductive treatment failure (Baram et al., 1988; Bryson et al., 2000
). Although the chance of spontaneous conception in the poor prognosis groups appears to be only half that of normal responders, the knowledge that conception can still occur naturally could be important for childless couples who have experienced IVF failure.
To our knowledge, this is the first study which compares the risk of early menopause between women who exhibit poor response to ovarian stimulation despite having a normal basal FSH level and those with a raised basal FSH level. It shows that poor response is a stronger indicator of declining ovarian function than raised FSH. Within 10 years of receiving IVF treatment, 30% of women with poor response had become menopausal compared with only 5% of women with raised basal FSH level (P = 0.015) and 0.3% of the control group (P = 0.002). The proportions of those who developed climacteric symptoms within the same period were 70, 50 and 26% respectively (P < 0.01).
In addition to menstrual cycle changes and vasomotor symptoms, a further sign of declining ovarian function is impaired fertility. Women who exhibited poor response to gonadotrophin stimulation achieved a lower pregnancy rate per assisted reproductive treatment cycle and a lower cumulative assisted reproductive treatment pregnancy rate than women with raised basal FSH level (9.2 versus 18.3% and 11.9 versus 23.2% respectively, OR 0.43, P = 0.01), providing further evidence that loss of female fertility and onset of menopause are reflections of the same process, namely progressive depletion of the oocyte pool.
It is known that female fertility declines with age (Menken et al., 1986; Margarelli et al., 1996
). However, it is also perceived that age per se can be a poor determinant of female fertility, since there is a wide range in the relationship between ovarian reserve and age (Jacobs et al., 1990
; Maroulis, 1991
).
Basal FSH concentration is an indirect estimate of ovarian reserve, being a measure of the magnitude of negative feedback exerted on the pituitary by ovarian inhibin and estradiol secretion (Buckler et al., 1991). Although an elevated basal FSH level has been shown to be a better predictor of poor IVF outcome and reproductive potential than chronological age alone (Toner et al., 1991
; Cahill et al., 1994
; Scott et al., 1995
), the significance of a normal FSH level in the early follicular phase in reflecting the true ovarian reserve and forecasting the risk of early menopause is undefined (Scott et al., 1990
; Schipper et al., 1998
). In this respect, measuring the clinical responsiveness of the ovaries to gonadotrophin stimulation appears to be a more sensitive and clinically useful tool. In the present study, poor responders and women with raised basal FSH levels were stimulated with a similar daily dose of gonadotrophins. However, the mean number of retrieved oocytes in the two groups was significantly different, reflecting the difference in the degree of oocyte pool depletion between the two groups (Lass et al., 1997
). Therefore, it seems reasonable to postulate that ovarian stimulation with gonadotrophins can be regarded as a dynamic test of ovarian reserve, similar to the clomiphene challenge test (Navot et al., 1987
; Scott and Hoffman, 1995
). Our results support this hypothesis: women with a normal basal FSH level who exhibited poor response to a high dose of gonadotrophin stimulation were nearly six times more likely to reach the menopause within 10 years of receiving IVF treatment than those with a raised basal FSH level. These findings are in agreement with the small study of Farhi et al. (1997
) which described a group of 12 normogonadotrophic women who did not respond to gonadotrophin stimulation and developed ovarian failure within a mean period of 9 months only (range 319).
Finally, our study found the highest incidence of pregnancy loss in the poor responders group (33%), although the inter-group difference approached, but did not reach, statistical significance (P = 0.07), due to the small number of pregnancies reported in the study. Abnormal chromosome complements are often found in ageing oocytes (Angell et al., 1991; Munné et al., 1995
; Magli et al., 1998
). It is also believed that primordial follicles which contain oocytes that are predisposed to aneuploidy are recruited predominantly late in reproductive life (Zheng and Byers, 1992
). Thus, the risk of aneuploidy increases with declining ovarian reserve. This hypothesis is supported by a casecontrol study of 78 spontaneously aborted fetuses, which found an association between abnormal karyotype and elevated maternal serum FSH and/or estradiol levels prior to conception (Nasseri et al., 1999
). In addition, various recent studies (Nikolettos et al., 2000
; Levi et al., 2001
; El-Toukhy et al., 2002
) have reported high miscarriage rates (4771%) in infertile patients with reduced ovarian reserve. Abnormal meiotic spindle assembly during various phases of meiosis has been demonstrated in ageing oocytes (Battaglia et al., 1996
; Steuerwald et al., 2001
) and could provide an explanation for this phenomenon.
Infertility is a chronic condition. Consequently, care of the infertile woman should not end with her last IVF attempt. So far, research has focused mainly on the immediate and short-term prognosis of infertility treatment, with only few studies addressing the risk of reproductive problems occurring well beyond the treatment period such as early onset of climacteric symptoms and menopause. The present study indicates a higher risk of early menopause occurring in poor responders to ovarian stimulation and in those with an elevated basal FSH level compared with normal responders. Indeed poor response appears to be a stronger predictor of such risk and, therefore implies a more profound degree of reduction in ovarian reserve. With such information, more informed counselling programmes, extending long after IVF treatment has ended, should be implemented. Both specialists and general practitioners should be alerted to the possibility of early menopause and its associated health risks in these women.
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Acknowledgements |
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References |
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Submitted on September 5, 2002; accepted on November 14, 2002.