IVF Unit, Hammersmith Hospital, Imperial College, London, UK
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Abstract |
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Key words: IVF/menopause/ovarian failure/ovarian reserve/poor response
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Introduction |
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In order to assess the ovarian reserve of an individual, various tests have been developed. These include day 3 FSH (Scott et al., 1989, 1995; Toner et al., 1991
; Sharif et al., 1998
), inhibin B (Seifer et al., 1997
, 1999
; Hofmannn et al., 1998), ovarian volume (Lass et al., 1997), the clomiphene citrate challenge test (Navot et al., 1987
; Loumaye et al., 1990
) and the GnRH agonist stimulation test (Galtier-Dereure et al., 1996
; Ranieri et al., 1998
). 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., 1998
). It is possible to use the information from an IVF cycle in order to predict an individual's reproductive potential (Van Rysselberge et al., 1989
; Jenkins et al., 1991
; Keay et al., 1997
; Lass et al., 1997b
). 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., 1997
; Karande and Gleicher, 1999
). 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., 1997
) 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 3443), 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 3540 years, is associated with an early ovarian failure.
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Materials and methods |
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Our IVF protocol has been described previously (Lass et al., 1997a, 1998a
). 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.
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Results |
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Discussion |
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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 3540 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 3035 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., 1997). 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., 1979
). 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., 1996
). 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 3540 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., 1998a). 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., 1998b
).
Our findings confirm that among asymptomatic, normally menstruating women aged 3540 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, 1999). Various medical, environmental (Sharara et al., 1998b
; Nicolopoulou-Stamati and Pitsos, 2001
) and genetic factors (Tibiletti et al., 1999
; 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., 1997
), 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., 1998
), 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., 1987), 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., 1998a
). 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, 2000
) 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., 1993
; Hofmann et al., 1996
). 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., 2001
). 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.
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Notes |
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References |
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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, 22172222.[Abstract]
Benadiva, C., Kligman, I. and Munné, S. (1996) Aneuploidy 16 in human embryos increases significantly with maternal age. Fertil. Steril., 66, 248255.[ISI][Medline]
Bopp, B. and Seifer, D. (1998) Oocyte loss and the perimenopause. Clin. Obstet. Gynaecol., 41, 898911.
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, 116124.[Abstract]
Check, J. (1999) Low and high responders| at what levels of serum estradiol do things start to get fuzzy? (Letters). Fertil. Steril., 71, 582583.[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.), S159S160.
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, 143148.[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, 3946.[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, 20142018.
Eppig, J. (1991) Intercommunication between mammalian oocytes and companion somatic cells. Bioessays, 13, 569574.[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, 13421346.[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, 241243.[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, 13931398.
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, 4953.[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, 474477.[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, 838844.[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, 358364.[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, 918921.[Abstract]
Karande, V. and Gleicher, N. (1999) A rational approach to the management of low responders in in-vitro fertilization: opinion. Hum. Reprod., 14, 17441748.
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, 521525.[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, 252254.[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, 835839[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, 294297.[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, 10281031.[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 fertilizationembryo transfer program. Fertil. Steril., 70, 10351038.[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, 10301034.[ISI][Medline]
Lim, A. and Tsakok, M. (1997) Age-related decline in fertility: a link to degenerative oocytes? Assist. Reprod. Technol., 68, 265271.
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, 295301.[ISI][Medline]
Munné, S. and Alikani, M. (1995) Embryo morphology, developmental rates and maternal age are correlated with chromosome abnormalities. Fertil. Steril., 64, 382391.[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, 8183.[Abstract]
Navot, D., Rosenwaks, Z. and Margalioth, E.J. (1987) Prognostic assessment of female fecundity. Lancet, ii, 645647.
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. LippincottRaven, Philadelphia.
Nicolopoulou-Stamati, P. and Pitsos, M. (2001) The impact of endocrine disrupters on the female reproductive system. Hum. Reprod. Update, 7, 323330.
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, 2935.
Padilla, S. and Garcia, J. (1990) Effect of maternal age and number of in vitro fertilization procedures on pregnancy outcome. Fertil. Steril., 52, 838844.
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, 674679.[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, 10151019.[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, 227233.[ISI][Medline]
Scott, R. and Hofmann, G. (1995) Prognostic assessment of ovarian reserve. Fertil. Steril., 63, 111.[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, 651654.[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, 539545.[Abstract]
Seifer, D. and Naftolin, F. (1998) Moving toward an earlier and better understanding of perimenopause. Fertil. Steril., 69, 387388.[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, 15311535.[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, 593598.[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, 110114.[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, 6365.[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, 257262.[ISI][Medline]
Sharara, F., Scott, R. and Seifer, D. (1998a) The detection of diminished ovarian reserve in infertile women. Am. J. Obstet. Gynecol., 179, 804812.[ISI][Medline]
Sharara, F., Seifer, D. and Flaws, J. (1998b) Environmental toxicants and female reproduction. Fertil. Steril., 70, 613622.[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, 107112.[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, 468478.[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, 27312734.
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, 784791.[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, 335337.[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, 663666.[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, 154160.[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, 236237.
Submitted on April 17, 2001; accepted on November 21, 2001.