Is there a link between an extremely poor response to ovarian hyperstimulation and early ovarian failure?

D. Nikolaou,1, S. Lavery, C. Turner, R. Margara and G. Trew

IVF Unit, Hammersmith Hospital, Imperial College, London, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: It has been previously reported that a group of 12 infertile women, who had a normal baseline hormonal profile and did not respond to repeated ovarian stimulation with gonadotrophins, developed ovarian failure within a few months. Based on this observation, we carried out a controlled retrospective cohort study to examine whether non-response to ovarian stimulation is linked to early ovarian failure. METHODS: All patients aged 35–40 years who had cancelled IVF cycles for non-response between 1991 and 1993 in our centre were asked to report on the subsequent development of menopausal symptoms, menopause or commencement of hormone replacement therapy. A control group consisted of patients with the same age and similar medical history, who had IVF the same year and responded well. RESULTS: Eleven out of the 12 patients of the non-response group developed menopausal symptoms within 7 years, compared with only four out of 24 in the control group. Similarly, eight out of 12 non-responders either went into menopause or started using hormone replacement therapy compared with one out of 24 in the control group. Using Fisher's exact test, the differences were highly significant (P < 0.0001). The median age at development of menopausal symptoms in the study group was 40 years (range 38–45). The median time between non-response and development of menopausal symptoms was 4 years (range 1–7). CONCLUSION: We carried out a controlled retrospective cohort study that showed a strong association between an extremely poor response to ovarian hyperstimulation and early ovarian failure.

Key words: IVF/menopause/ovarian failure/ovarian reserve/poor response


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Traditionally, the perimenopause was described as the time when ovarian function was so altered by the continuous depletion of oocytes that clinical symptoms, such as menstrual irregularities, appeared. In recent years, assisted reproductive technologies have given us a better understanding of the events that precede the menopause (Seifer and Naftolin, 1998Go). It is now realized that an accelerated decline of ovarian function begins much earlier than previously thought, most likely in the mid-thirties (Bopp and Seifer, 1998Go). At around this time the total remaining number of follicles in the ovaries has been shown to be near 25000 (Faddy et al., 1992Go) and there is an accelerated loss of follicles, as well as qualitative changes in the remaining follicles. These follicles have fewer granulosa cells, which demonstrate diminished production of steroids and glucoproteins (Hughes and Robertson, 1990Go; Buckler et al., 1991Go; Seifer et al., 1999Go) and also decreased mitosis and increased apoptosis (Seifer et al., 1993GoSeifer et al., 1996a). As a result of compromised endocrine, paracrine and autocrine signals, there is altered communication between the granulosa cells and the oocytes, which result in abnormal nuclear and cytoplasmic maturation within the oocyte (Eppig, 1991Go; Munné et al., 1995; Battaglia et al., 1996Go; Lim and Tsakok, 1997Go; Volarcik et al., 1998Go). The clinical result is an increase in the incidence of aneuploidy (Benadiva et al., 1996Go), an increase in the incidence of miscarriage and a decrease in fertility rates both spontaneous and with assisted reproduction technologies (Sharma et al., 1988Go; Hughes et al., 1989Go; Padilla et al., 1990). This marked reduction of reproductive potential occurs without obvious clinical symptoms of endocrine deficiency. The term used to describe a woman's reproductive potential, as it relates to the process of follicular depletion and oocyte quality, is ovarian reserve. It is well established that, in general, ovarian reserve declines with age. However, the rate of this decline seems to vary among individuals and depends on the medical history and various environmental and genetic factors. Severe endometriosis, pelvic inflammatory disease, ovarian surgery, various systemic illnesses, chemotherapy and smoking are all known factors affecting the ovarian reserve (Wardle et al., 1985Go; Khalifa et al., 1992Go; Sharara et al., 1994Go; Nargund et al., 1995Go; Keay et al., 1998Go; Lass et al., 1998aGo).

In order to assess the ovarian reserve of an individual, various tests have been developed. These include day 3 FSH (Scott et al., 1989Go, 1995; Toner et al., 1991Go; Sharif et al., 1998Go), inhibin B (Seifer et al., 1997Go, 1999Go; Hofmannn et al., 1998), ovarian volume (Lass et al., 1997), the clomiphene citrate challenge test (Navot et al., 1987Go; Loumaye et al., 1990Go) and the GnRH agonist stimulation test (Galtier-Dereure et al., 1996Go; Ranieri et al., 1998Go). All these tests were originally developed in order to predict an individual's chances of success using assisted conception. The way a woman's ovaries respond to stimulation with gonadotrophins during IVF treatment is in itself a dynamic assessment of the ovarian reserve (Phelps et al., 1998Go). It is possible to use the information from an IVF cycle in order to predict an individual's reproductive potential (Van Rysselberge et al., 1989Go; Jenkins et al., 1991Go; Keay et al., 1997Go; Lass et al., 1997bGo). Once a patient has responded poorly to ovarian stimulation, her chance of pregnancy in future IVF cycles is low and the chances of future cycle cancellations high. Various stimulation protocols have been proposed to increase the success rate of `poor responders', but so far none of these strategies has been very successful (Keay et al., 1997Go; Karande and Gleicher, 1999Go). Although there is evidence that poor performance in the various dynamic tests for ovarian reserve, including IVF, is associated with low pregnancy rates, there has not been evidence, so far, that this poor performance is also linked to an earlier menopause. One interesting study (Farhi et al., 1997Go) reported the identification of a group of 12 infertile women, initially diagnosed as having unexplained or anovulatory infertility, who had a normal baseline hormonal profile and did not respond to repeated ovarian stimulation with gonadotrophins. They all developed ovarian failure within a few months. The mean age of the patients in that group was 39.8 years (range 34–43), the mean FSH at first evaluation was 5.4 IU/l and, following the diagnosis of non-response, 53.5 IU/l. The mean time elapsed between the two tests was 8.8 months. They concluded that non-response to gonadotrophin stimulation might be the first detectable sign of impending menopause. Based on this interesting observation, we carried out the present study. Our question was whether an extremely poor response to ovarian stimulation, in otherwise asymptomatic women aged 35–40 years, is associated with an early ovarian failure.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We conducted a controlled retrospective cohort study. The clinical notes of all the patients who had cancelled IVF cycles for poor response in our centre between 1991 and 1993 were reviewed. Only patients aged 35–40 years who had an extremely poor response were included in this study. We accepted as extremely poor response (`non-response') the absence of follicles >10 mm diameter on vaginal ultrasound or a peak estrogen level of <300 pmol/l, despite receiving >=150 IU of HMG for >=9 days, i.e. 1350 IU of HMG. We accepted either the menopause, i.e. complete cessation of periods for 1 year or the commencement of hormone replacement therapy (HRT) as the definition of ovarian failure. The reason is that many patients started HRT before their periods ceased completely. All patients were sent questionnaires asking about cessation of periods, commencement of HRT and onset of menopausal symptoms, namely irregular periods, hot flushes, night-sweats, insomnia, constant tiredness and depression.

Our IVF protocol has been described previously (Lass et al., 1997aGo, 1998aGo). Briefly, the pituitary was down-regulated with GnRH analogues for 2 weeks and the patients then had a vaginal ultrasound and a blood test to measure estradiol levels. If the endometrial thickness was <5 mm and the estrogen level <100 pmol/l, the ovarian stimulation started, using HMG. The estrogen level was checked on day 5 of ovarian stimulation and if it was low, the dose of HMG was increased at that stage. The patient was seen again on day 9 of HMG and had a vaginal ultrasound and a blood test for estrogen level. Blood tests were done daily thereafter and a vaginal scan was performed on day 12 of HMG and every second day thereafter. If the response was poor, the dose of HMG was increased. Each patient in the non-response group was matched with two other patients who had IVF treatment the same year and no history of cancelled cycles for poor response. They were all sent questionnaires. We identified controls with the same age and cause of infertility with the patients of the non-response group. For statistical analysis we used Fisher's exact test with the assistance of Prism software, taking P < 0.05 as significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 24 patients who had cancelled IVF cycles for non-response were initially identified and sent questionnaires, of which 18 replied (response rate 75%). One patient had menopausal symptoms and high FSH before the non-response cycle and was excluded from the analysis. Five more patients had unilateral oophorectomies and were also excluded. Finally, 12 patients remained in the study group and were matched with 24 controls. The median age in both groups was 37 years (range 35–39). The cause of infertility was tubal factor in nine cases, male in one case and unexplained in two cases. All the women had regular menstrual cycles with no symptoms of climacteric. The median amount of HMG that had actually been used before the cycle was abandoned was 3400 IU (range 2625–8400). In the study group, 11 out of 12 patients started having menopausal symptoms within 7 years from the non-response cycle (91.6%), whereas in the control group only four out of 24 patients started having menopausal symptoms (16.6%, Table IGo). Similarly, in the study group eight out of 12 patients either went into menopause or started HRT (66.6%) compared with one out of 24 patients in the control group (4.16%, Table IIGo). Using Fisher's exact test, the differences were statistically significant (P < 0.0001). In the study group, the median age of onset of menopausal symptoms was 40 years [range 38–45, mean 41.2, 95% confidence interval (CI) 39.3–42.9, passed normality test]. The median age of cessation of periods or commencement of HRT was 40 years (range 38–45, mean 41.3, 95% CI 39.0–43.7, passed normality test) (Table IIIGo). The median time between the non-response cycle and onset of menopausal symptoms in the study group was 4 years (range 1–7, mean 3.7, 95% CI 2.3–5.0, passed normality test). The median time between the non-response cycle and menopause or commencement of HRT was 4 years (range 1–6, mean 4.2, 95% CI 2.9–5.5, passed normality test).


View this table:
[in this window]
[in a new window]
 
Table I. Menopausal symptoms within 7 years of ovarian stimulation cycle
 

View this table:
[in this window]
[in a new window]
 
Table II. Menopause or hormone replacement therapy (HRT) within 7 years of ovarian stimulation cycle
 

View this table:
[in this window]
[in a new window]
 
Table III. Characteristics of patients having menopausal symptoms within 7 years from the non-response cycle
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study provides controlled information further supporting the concept that the development of ovarian insufficiency is a continuum. The continuum's earliest sign is a poor response to gonadotrophin stimulation and the end stage is the development of ovarian failure. There is no standard definition of poor response to ovarian stimulation. It generally implies failure to achieve a certain number of mature follicles or a certain estrogen level in relation to the amount of ovarian stimulation that has been given (Keay et al., 1997Go). Different authors have used different definitions of poor response (Jenkins et al., 1991Go; Keay et al., 1997Go; Karande and Gleicher, 1999Go). It is easier to understand non-response and we decided to take this extreme situation as our starting point. It is possible that women who do not respond well to a relatively low dose of gonadotrophins will respond better to a higher dose, but it has been shown that increasing the dose beyond a certain level rarely improves the outcome (Out et al., 2000Go). Our study group had used, on average, much higher doses of HMG (3400 IU) than our original minimum inclusion criteria and had no response at all.

The total number of patients in the present study is admittedly small, but the differences are very clear. The strength of the study is that there was a control group. Women who did not respond to stimulation developed menopausal symptoms. Women of the same age, who responded to stimulation, did not develop menopausal symptoms. Because there is already evidence that the accelerated operational decline of the ovarian follicular apparatus usually starts in the mid-thirties, we decided to investigate women aged 35–40 years in this particular study. Fertility in the late thirties is generally an issue that is becoming more and more prominent and it was therefore relevant to observe the way the ovaries respond in this particular age group. We are currently studying poor responders aged 30–35 years.

All the women in the `non-response' group were menstruating normally before their non-response cycle and none had any symptoms of the climacteric. There was only one patient who had experienced vasomotor symptoms prior to the non-response cycle and she was excluded from the study. At the time when these IVF cycles were taking place, it was not our policy to check the day 3 FSH of the treatment cycle, so the data on FSH were incomplete. However, in most cases where we did have data, day 3 FSH had been <10 IU/l until the non-response cycle and were >10 IU/l later. This is in keeping with previous findings (Farhi et al., 1997Go). Like other studies that rely on recollection of menstrual detail or age at menopause, it is possible that our study was subject to errors of recall (Bean et al., 1979Go). For example, there did not appear to be a significant time lag overall between onset of menopausal symptoms and ovarian failure. It is also possible that, unlike the normal menopause that is usually preceded by the `climacteric', there is not always a characteristic antecedent menstrual history for either early or premature ovarian failure. Many patients with premature ovarian failure develop amenorrhoea acutely after having established regular menses (Nelson et al., 1996Go). Ovarian function may return intermittently and unpredictably in these patients.

Some women of our non-response group attempted IVF again following their non-response cycle, using combinations of drugs in high doses and various protocols. Some reached oocyte retrieval, but none of them achieved a clinical pregnancy. It seems reasonable, therefore, to suggest that an extremely poor response to ovarian stimulation at the age of 35–40 years, apart from being associated with very poor chances of pregnancy in future IVF attempts, is also linked to an early menopause. However, it is difficult to comment on whether a good response to IVF, especially in older women, predicts a late menopause. The various existing tests for ovarian reserve generally have good specificity but rather poor sensitivity. Although abnormal results predict poor responses, there are women, especially older women, who have good test results but respond poorly to ovarian stimulation. In previous studies, stratified and multivariate logistic regression analyses indicated that, although basal FSH level exerted a measurable impact on pregnancy rates, chronological age was also an independent determinant of outcome (Pearlstone, 1992). The mechanisms by which chronological age could diminish pregnancy rates independent of FSH are not fully understood. Similarly with the clomiphene citrate challenge test: although it is quite specific, it has limited sensitivity, with a significant age-related diminution in reproductive potential occurring even among women with normal test results (Sharara et al., 1998aGo). On the other hand there has been research in our unit, looking at >1000 IVF cycles in women aged >40 years, showing that older women who respond well to ovarian stimulation with gonadotrophins have a reasonable chance of achieving a pregnancy, despite their age (Lass et al., 1998bGo).

Our findings confirm that among asymptomatic, normally menstruating women aged 35–40 years there are some who, compared with others of exactly the same age, have a very poor ovarian reserve. We do not know the prevalence and the exact mechanism of premature decline of ovarian reserve, especially in terms of oocyte quality, in the general population. One possible mechanism is a generally higher intrinsic rate of atresia. Another possibility is that some patients have had a destructive process that left behind fewer follicles but the same proportion of `good' oocytes (Check, 1999Go). Various medical, environmental (Sharara et al., 1998bGo; Nicolopoulou-Stamati and Pitsos, 2001Go) and genetic factors (Tibiletti et al., 1999Go; de Bruin et al., 2001) may be involved. An interesting hypothesis is that this process may have occurred in fetal life. In an epidemiological study (Cresswell et al., 1997Go), menopause occurred at a younger age in women who had low weight at 1 year. Women who had an early menopause tended to have been short at birth, with a high ponderal index. It was suggested that growth retardation in late gestation, leading to shortness at birth and low weight gain in infancy, might be associated with a reduced number of primordial follicles in the ovary, leading to an earlier menopause. In another study (De Bruin et al., 1998Go), the volume percentages of primordial follicles in the ovaries of severely growth-retarded fetuses of different gestational ages were significantly lower than those observed in age-matched controls.

The concept of ovarian reserve screening has been discussed since 1987 (Navot et al., 1987Go), mainly in the context of infertility investigations and for predicting IVF outcome. It has been suggested that infertile patients should have their ovarian reserve assessed early in their infertility (Scott et al., 1995) and there is now a wider consensus that this is especially indicated for every patient aged >=35 years and for cases of unexplained infertility (Sharara et al., 1998aGo). Many women delay their families until their thirties for personal and/or professional reasons and there is also a growing rate of divorce and remarriage. There is evidence that the rapid decline of ovarian reserve starts in the mid-thirties for most women. As it is almost certain that this rapid decline starts even earlier (possibly in the early thirties) in a proportion of the general population that is still unknown, there may be a scope for evaluating screening methods of ovarian reserve for asymptomatic women starting from the early thirties. This could then be used to develop prevention strategies for subfertility, menorrhagia, pregnancy complications in the context of preconceptional counselling, psychological morbidity, osteoporosis and early menopause. It has been shown that diminished ovarian reserve is associated with unexplained recurrent miscarriage (Trout and Seifer, 2000Go) and there has also been evidence that many cases of `unexplained' infertility are in fact caused by an early decline of the ovarian reserve (Scott et al., 1993Go; Hofmann et al., 1996Go). In a very interesting report, diminished ovarian reserve in normally cycling women was a predictor of unfavourable lipid levels and increased cardiovascular risk (Chu et al., 2001Go). An exciting area of research would be to investigate the possibility of delaying or even reversing the accelerated decline of the ovarian reserve in some women.

In conclusion, we conducted a controlled retrospective cohort study, which showed a strong association between an extremely poor response to ovarian stimulation and early ovarian failure.


    Notes
 
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Foresterhill, Aberdeen AB25 2ZD, UK. E-mail: dnikolaou{at}talk21.com Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Bean, J.A., Leeper, J.D., Wallace, R.B., Sherman, B.M. and Jagger, H. (1979) Variations in the reporting of menstrual histories. Am. J. Epidemiol., 109, 181–185.[Abstract]

Battaglia, D.E., Goodwin, P., Klein, N.A. and Soules, M.R. (1996) Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women Hum. Reprod., 11, 2217–2222.[Abstract]

Benadiva, C., Kligman, I. and Munné, S. (1996) Aneuploidy 16 in human embryos increases significantly with maternal age. Fertil. Steril., 66, 248–255.[ISI][Medline]

Bopp, B. and Seifer, D. (1998) Oocyte loss and the perimenopause. Clin. Obstet. Gynaecol., 41, 898–911.

Buckler, H., Evans, C., Mamtora, H., Burger, H.G. and Anderson, D.C. (1991) Gonadotropin, steroid, and inhibin levels in women with incipient ovarian failure during anovulatory and ovulatory rebound cycles. J. Clin. Endocrinol. Metabol., 72, 116–124.[Abstract]

Check, J. (1999) Low and high responders| at what levels of serum estradiol do things start to get fuzzy? (Letters). Fertil. Steril., 71, 582–583.[Medline]

Chu, M., Rath, K. and Taylor, H. (2001) Diminished ovarian reserve in normal cycling women is a predictor of unfavourable lipid levels and increased cardiovascular risk. Fertil. Steril., 76 (Suppl.), S159–S160.

Cresswell, J., Egger, P., Fall, C.H.D., Osmond, C., Fraser, R.B. and Barker, D.J.P. (1997) Is the age of menopause determined in utero? Early Hum. Dev., 49, 143–148.[ISI][Medline]

De Bruin, J., Dorland, M., Bruinse, H.W., Spliet, W., Nikkels, P.G.J. and Te Velde, E.R. (1998) Fetal growth retardation as a cause of impaired ovarian development. Early Hum. Dev., 51, 39–46.[ISI][Medline]

De Bruin, J.P., Bovenhuis, H., van Noord, P.A.H, Pearson, P.L., van Arendonk, J.A.M., te Velde, E.R., Kuurman, W.W. and Dorland, M. (2001) The role of genetic factors in age at natural menopause. Hum. Reprod., 16, 2014–2018.[Abstract/Free Full Text]

Eppig, J. (1991) Intercommunication between mammalian oocytes and companion somatic cells. Bioessays, 13, 569–574.[ISI][Medline]

Faddy, M., Gosden, R., Gougeon, A., Richardson, S. and Nelson, J. (1992) Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum. Reprod., 7, 1342–1346.[Abstract]

Farhi, J., Homburg, R., Ferber, A., Orvieto, R. and Ben-Rafael, Z. (1997) Non response to ovarian stimulation in normogonadotrophic, normogonadal women: a clinical sign of impending onset of ovarian failure pre-empting the rise in basal follicle stimulating hormone levels. Hum. Reprod., 12, 241–243.[Abstract]

Galtier-Dereure, F., De Bouard, V., Picot, M.C., Vergnes, C., Humeau, C., Bringer, J. and Hedon, B. (1996) Ovarian reserve test with gonadotrophin-releasing hormone agonist Buserelin: correlation with in-vitro fertilization outcome. Hum. Reprod., 11, 1393–1398.[Abstract/Free Full Text]

Hofmann, G.E., Sosnowski, J., Scott, R.T. and Thie, J. (1996) Efficacy of selection criteria for ovarian reserve screening using the clomiphene citrate challenge test in a tertiary fertility centre population. Fertil. Steril., 66, 49–53.[ISI][Medline]

Hofmann, G., Danforth, D. and Seifer, D. (1998) Inhibin-B: the physiologic basis of the clomiphene citrate challenge test for ovarian reserve screening. Fertil. Steril., 69, 474–477.[ISI][Medline]

Hughes, E., King, C. and Wood, E.C. (1989) A prospective study of prognostic factors in in-vitro fertilization and embryo transfer. Fertil. Steril., 51, 838–844.[ISI][Medline]

Hughes, E.G., Robertson, D.M., Handelsman, D.J., Hayward, S., Healy, D.L. and de Kretser, D.M. (1990) Inhibin and oestradiol responses to ovarian hyperstimulation: effects of age and predictive value for in vitro fertilization outcome. J. Clin. Endocrinol. Metab., 70, 358–364.[Abstract]

Jenkins, J.M., Davies, D.W., Devonport, H., Anthony, F.W., Gadd, S.C., Watson, R.H. and Masson, G.M. (1991) Comparison of `poor' responders with `good responders' using a standard buserelin/human menopausal gonadotrophin regime for in-vitro fertilization. Hum. Reprod., 6, 918–921.[Abstract]

Karande, V. and Gleicher, N. (1999) A rational approach to the management of low responders in in-vitro fertilization: opinion. Hum. Reprod., 14, 1744–1748.[Free Full Text]

Keay, S.D., Liversedge, N.H., Mathur, R.S. and Jenkins, J.M. (1997) Assisted conception following poor ovarian response to gonadotrophin stimulation. Br. J. Obstet. Gynaecol., 104, 521–525.[ISI][Medline]

Keay, S.D., Liversedge, N.H. and Jenkins, J.M. (1998) Could ovarian infection impair ovarian response to gonadotrophin stimulation? Br. J. Obstet. Gynaecol., 105, 252–254.[ISI][Medline]

Khalifa, E., Toner, J.P., Muasher, S.J. and Acosta, A.A. (1992) Significance of basal follicle stimulating hormone in women with one ovary in a program of in vitro fertilization. Fertil. Steril., 57, 835–839[ISI][Medline]

Lass, A., Skull, J., McVeigh, E., Margara, R. and Winston, R.M. (1997a) Measurement of ovarian volume by transvaginal sonography before human menopausal gonadotrophin superovulation for in-vitro fertilization can predict poor response. Hum. Reprod., 12, 294–297.[Abstract]

Lass, A., Silye, R., Abrams, D.C., Krautz, T., Hovatta, O., Margara, R. and Winston, R.M. (1997b) Follicular density in ovarian biopsy of infertile women: a novel method to assess ovarian reserve. Hum. Reprod., 12, 1028–1031.[ISI][Medline]

Lass, A., Ellenbogen, A., Croucher, C., Trew, G., Margara, R., Becattini, C. and Winston, R.M. (1998a) Effect of salpingectomy on ovarian response to superovulation in an in-vitro fertilization–embryo transfer program. Fertil. Steril., 70, 1035–1038.[ISI][Medline]

Lass, A., Croucher, C., Duffy, S., Dawson, K., Margara, R. and Winston, R.M. (1998b) One thousand initiated cycles of in-vitro fertilization in women >=40 years of age. Fertil. Steril., 70, 1030–1034.[ISI][Medline]

Lim, A. and Tsakok, M. (1997) Age-related decline in fertility: a link to degenerative oocytes? Assist. Reprod. Technol., 68, 265–271.

Loumaye, E., Billion, J-M., Mine, J.M., Psalti, I., Pensis, M. and Thomas, K (1990) Prediction of individual response to controlled ovarian hyperstimulation by means of a clomiphene citrate challenge test. Fertil. Steril., 53, 295–301.[ISI][Medline]

Munné, S. and Alikani, M. (1995) Embryo morphology, developmental rates and maternal age are correlated with chromosome abnormalities. Fertil. Steril., 64, 382–391.[ISI][Medline]

Nargund, G., Cheng, W.C. and Parsons, J. (1995) The impact of ovarian cystectomy on ovarian response to stimulation during in vitro fertilization cycles. Hum. Reprod., 11, 81–83.[Abstract]

Navot, D., Rosenwaks, Z. and Margalioth, E.J. (1987) Prognostic assessment of female fecundity. Lancet, ii, 645–647.

Nelson, L..M., Anasti, J.N. and Flack, M.R (1996) Premature ovarian failure. In Adashi, E.Y., Rock, J.A. and Rozenwaks, Z. (eds). Reproductive Endocrinology, Surgery and Technology. Lippincott–Raven, Philadelphia.

Nicolopoulou-Stamati, P. and Pitsos, M. (2001) The impact of endocrine disrupters on the female reproductive system. Hum. Reprod. Update, 7, 323–330.[Abstract/Free Full Text]

Out, H.J., Braat, D.D., Lintsen, R.M., Gurgan, T., Bukulmez, O., Gokmen, O., Keles, G., Caballero, P., Gonzalez, J.M., Ferbegues, F. et al. (2000) Increasing the daily dose of recombinant follicle stimulating hormone (Puregon) does not compensate for the age-related decline in retrievable oocytes after ovarian stimulation. Hum. Reprod., 15, 29–35.[Abstract/Free Full Text]

Padilla, S. and Garcia, J. (1990) Effect of maternal age and number of in vitro fertilization procedures on pregnancy outcome. Fertil. Steril., 52, 838–844.

Pearlstone, A.C., Fournet, N., Gambone, J.C., Pang, S.C. and Buyalos, R.P. (1992) Ovulation induction in women age 40 and older: the importance of basal follicle-stimulating hormone level and chronological age. Fertil. Steril., 58, 674–679.[ISI][Medline]

Phelps, J., Levine, A., Hickman, T., Zacur, H., Wallach, E. and Hinton, E. (1998) Day 4 estradiol levels predict pregnancy success in women undergoing controlled ovarian hyperstimulation for IVF. Fertil. Steril., 69, 1015–1019.[ISI][Medline]

Ranieri, D.M., Quinn, F., Makhlouf, A., Kkadum, I., Ghutmi, W., McGarrigle, A., Davies, M. and Serhal, P. (1998) Simultaneous evaluation of basal follicle-stimulating hormone and 17-ß-estradiol response to gonadotropin-releasing hormone analogue stimulation: an improved predictor of ovarian reserve. Fertil. Steril., 70, 227–233.[ISI][Medline]

Scott, R. and Hofmann, G. (1995) Prognostic assessment of ovarian reserve. Fertil. Steril., 63, 1–11.[ISI][Medline]

Scott, R., Toner, J., Muasher, S.J., Oehninger, S., Robinson, S. and Rosenwaks, Z. (1989) Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome. Fertil. Steril., 51, 651–654.[ISI][Medline]

Scott, R.T., Leonardi, M.R., Hofman, G.E., Illions, E.H., Neal, G.S. and Navot, D. (1993) A prospective evaluation of clomiphene citrate challenge test screening in the general infertility population. Obstet. Gynaecol., 82, 539–545.[Abstract]

Seifer, D. and Naftolin, F. (1998) Moving toward an earlier and better understanding of perimenopause. Fertil. Steril., 69, 387–388.[ISI][Medline]

Seifer, D., Charland, C., Berlinsky, D., Penzias, A., Haning, R., Naftolin, F. and Barker, B. (1993) Proliferative index of human luteinized granulosa cells varies as a function of ovarian reserve. Am. J. Obstet. Gynaecol., 169, 1531–1535.[ISI][Medline]

Seifer, D., Gardiner, A., Ferreira, K. and Peluso, J. (1996) Apoptosis as a function of ovarian reserve in women undergoing in-vitro fertilization. Fertil. Steril., 66, 593–598.[ISI][Medline]

Seifer, D., Lambert-Messerlian, G., Hogan, J.W., Gardiner, A., Blazar, A. and Berk, C. (1997) Day 3 serum inhibin-B is predictive of assisted reproductive technologies outcome. Fertil. Steril., 67, 110–114.[ISI][Medline]

Seifer, D., Scott, R., Bergh, P.A., Abogast, L.K., Fiedman, C.I., Mack, C.K. and Danforth, D.R. (1999) Women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin B before a rise in day 3 follicle-stimulating hormone. Fertil. Steril., 72, 63–65.[ISI][Medline]

Sharara, F.I., Beatse, S.N., Leonardi, M.R., Navot, D. and Scott, R.T. (1994) Cigarette smoking accelerates the development of diminished ovarian reserve as evidenced by clomiphene citrate challenge test. Fertil. Steril., 62, 257–262.[ISI][Medline]

Sharara, F., Scott, R. and Seifer, D. (1998a) The detection of diminished ovarian reserve in infertile women. Am. J. Obstet. Gynecol., 179, 804–812.[ISI][Medline]

Sharara, F., Seifer, D. and Flaws, J. (1998b) Environmental toxicants and female reproduction. Fertil. Steril., 70, 613–622.[ISI][Medline]

Sharif, K., Elgendy, M., Lashen, H. and Afnan, M. (1998) Age and basal stimulating hormone as predictors of in vitro fertilization outcome. Br. J. Obstet. Gynaecol., 105, 107–112.[ISI][Medline]

Sharma, V., Riddle, A., Mason, B.A., Pampiglione, J. and Campbell, S. (1988) An analysis of factors influencing the establishment of a clinical pregnancy in an ultrasound-based ambulatory in vitro fertilization program. Fertil. Steril., 49, 468–478.[ISI][Medline]

Tibiletti, M., Testa, G., Vegetti, W., Alagna, F., Taborelli, M., Dalp, L., Bolis, P.F. and Cosignani, P.G. (1999) The idiopathic forms of premature menopause and early menopause show the same genetic pattern. Hum. Reprod., 14, 2731–2734.[Abstract/Free Full Text]

Toner, J., Philput, C., Jones, G. and Muasher, S. (1991) Basal follicle-stimulating hormone level is a better predictor of in vitro fertilization performance than age. Fertil. Steril., 55, 784–791.[ISI][Medline]

Trout, S. and Seifer, D. (2000) Do women with unexplained recurrent pregnancy loss have higher day 3 serum FSH and estradiol values? Fertil. Steril., 74, 335–337.[ISI][Medline]

Van Rysselberge, M., Puissant, F., Barlow, P., Lejeune, B., Delvigne, A. and Leroy, F. (1989) Fertility prognosis in IVF treatment of patients with cancelled cycles. Hum. Reprod., 4, 663–666.[Abstract]

Volarcik, K., Sheean, L., Goldfarb, J., Woods, L., Abdul-Karim, F.W. and Hunt, P. (1998) The meiotic competence of in-vitro matured human oocytes is influenced by donor age: evidence that folliculogenesis is compromised in the reproductively aged ovary. Hum. Reprod., 13, 154–160.[Abstract]

Wardle, P.G., McLaughlin, E.A., McLaughlin, E.A., Ray, B.D., McDermott, A. and Hull, M.G. (1985) Endometriosis and ovulatory disorder: reduced fertilization in vitro compared with tubal and unexplained infertility. Lancet, ii, 236–237.

Submitted on April 17, 2001; accepted on November 21, 2001.