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The impact of age on reproductive potential: lessons learned from oocyte donation
Maturitas 30 (1998) 221 – 225
The impact of age on reproductive potential: lessons learned from oocyte donation Mark V. Sauer * Professor and Chief, Di6ision of Reproducti6e Endocrinology and Infertility, Department of Obstetrics and Gynaecology, College of Physicians and Surgeons, Columbia Uni6ersity, New York, NY, USA
Abstract Objecti6e: Oocyte donation allows a unique opportunity to separately study the effect of aging on uterine receptivity and oocyte quality. The purpose of this report is to review the published experience on reproductive aging in both laboratory animals and humans as it pertains to oocyte and embryo donation. Methods: A review of the published medical literature. Results: Natural fertility rates decline in most animals with age, becoming dramatically apparent in women as they enter the fifth decade of life. By the time of the perimenopause, pregnancy rarely occurs, whether or not assisted reproductive techniques are initiated. However, if oocytes are donated by young women to older women, both embryo implantation and pregnancy rates are restored to normal levels in recipients. Conclusions: These results strongly suggest the pregnancy wastage experienced by older women is largely a result of degenerative changes within the aging oocyte, rather than senescent changes in the uterus. The poor prognosis for fertility in older women can be reversed through oocyte donation from younger individuals. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Oocyte donation; Perimenopause; Advanced maternal age; Implantation
1. Introduction Fecundability rates vary among populations as a result of cultural, religious, and sexual practices. Typically, women conceive and deliver while in their twenties, with most conceptions occurring * Corresponding author. Columbia Presbyterian Medical Center, 622 West 168th Street, PH16-28, New York, NY, 10032-3784. USA. Tel.: +1 212 3059175; fax: + 1 212 3053869.
within the first six months of unprotected intercourse. Fertility rates begin to fall during the fourth decade of life and reach a nadir after the age of 40 years [1]. Further complicating the decreasing fertility rate is an alarming rise in aneuploidy in the concepti of aging females. This exaggerates the miscarriage rate and increases the number of observed anomalies in delivered offspring. For example, at age 25 years the risk of a spontaneous abortion following the clinical diagnosis of preg-
0378-5122/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0378-5122(98)00077-2
M.V. Sauer / Maturitas 30 (1998) 221–225
222
Table 1 Results of in-vitro fertilization procedures by age as reported to the National Registry of the American Society for Reproductive Medicine Age patients (years)
Retrievals
Canceled (%)
No. pregnancies
Deliveries/retrieval (%)
B35 35–39 \39
11 949 9317 4096
11.8 17.7 25.2
3826 2559 686
27.5 21.6 10.6
Modified from Fertil Steril 69: 389–398, 1998.
nancy is approximately 10% [2]. By 45 years of age, nearly half of all clinical pregnancies end in miscarriage. Pregnancy wastage is likely a result of spontaneous mutations in resting oocytes. Close to 50% of ova karyotyped in women over the age of 35 years undergoing in vitro fertilization are aneuploid [3]. Similarly, cytogenetic studies of metaphase II oocytes using FISH detect a high rate of disomy for chromosome 21 in women over the age of 40 years [4]. Likewise, a high percentage of abortuses of older mothers are chromosomally abnormal [5]. Thus, preand post-implantation losses protect the species from unwanted genetic mutations and may be thought of as natural selection against gross anomalies. Generally, women over the age of 40 years seeking fertility care have limited success. Reviewing the annual statistics for cases reported in the USA to the National IVF-ET Registry, low birth rates are noted (Table 1) [6]. However, these published statistics actually overestimate success, since many women initially enter treatment and are dropped from therapy due to a poor response to controlled ovarian hyperstimulation.
2. Ovarian age and reproduction It appears evolution precludes most women from reproducing after the age of 40 years. Certainly by age 50 years the majority of women experience menopause and the complete cessation of ovulatory function. Unlike other mammals, the ovaries in humans have nearly exhausted their supply of oocytes by the time menopause occurs [7]. Yet, fewer than 0.001% of the ovary’s original
complement of oocytes are ever ovulated. Most oocytes undergo apoptosis and atresia, which is the process by which oocytes and their follicles are removed. Histologic studies indicate that at the time of menopause, regardless of the chronologic age of the individual, at most only a few thousand eggs are left [8]. Despite the compensatory rise in stimulating pituitary gonadotropin, this cohort is unlikely to be recruited. Cadaver studies note a decline in follicular mass with advancing age and insinuate that accelerated rates of follicular atresia occur during the last decade of reproductive life before menopause. Interestingly, the largest turnover of oocytes occurs before birth. A steady decline from approximately 7 million oocytes at 20 weeks gestation, to around 2 million at the time of delivery is reported [9]. By menarche only 300000 eggs are estimated to remain, and by menopause women have virtually no primordial follicles remaining [7].
3. Animal models for reproductive aging The uteri of laboratory animals undergo age-related changes that accompany a fall in implantation and pregnancy rates. Older animals eventually are unable to achieve pregnancy despite the transfer of embryos from younger animals [10]. Similarly, in other studies older mice have been noted to have fewer implantation sites, and are twice as likely to resorb an early pregnancy compared to younger animals [11]. Correlates using other rodent models also exist, including a reduction in litter size in the aging hamster [12].
M.V. Sauer / Maturitas 30 (1998) 221–225
223
Table 2 Success rates for functionally agonadal women of various ages given hormone replacement therapy and transferred embryos following oocyte donation Age group (years)
No. cases performed
Implant. rate (%)
Resorption rate (%)
Del PR (%)
Cum PR (%)
B30 30–39 40–49 50–59
13 89 177 21
11.1 15.1 15.2 17.9
33.3 30.5 45.4 31.6
32.0 31.3 29.5 37.5
50.0 47.5 52.3 55.6
Implant. rate, implantation rate/embryo transferred; resorption rate, number of implanted embryos that spontaneously resorbed prior to delivery; del PR, delivery rate/embryo transfer performed; cum PR, cumulative pregnancy rate/patient group over time. Modified from J Asst Reprod Genet 11:92–96, 1994.
Many possible factors influence the relationship between the early conceptus and the endometrial environment. These include the rate and normal pattern of development of ova in the older female reproductive tract, delayed uterine sensitivity to blastocyst implantation secondary to a decreased capacity of older uterine tissue to take up steroids, and the less efficient uterine response to a decidualizing stimulus as seen in the mouse, rat, and hamster [13]. Thus, in rodents, an age-related decline in fertility as the result of a ‘uterine factor’ appears to exist, as evidenced by implantation failure leading to infertility and prenatal mortality.
4. Uterine aging and human reproduction It is suggested that the age-related decline in human fertility is partly due to a ‘uterine factor’ [14]. Uterine receptivity may be measured by comparing embryo implantation rates in humans of various ages undergoing in vitro fertilization and embryo transfer. Women under the age of 30 years approach rates as favorable as 20%/embryo transferred, decreasing to B10% in women 36 years of age and older [15]. After the age of 40 years, individual embryo implantation rates are but 5% [16]. Uterine blood flow decreases with declining levels of estradiol, as naturally occurs with menopause, which may adversely affect the local endometrial environment [17]. The identification of estrogen receptors in the wall of human uterine arteries is supportive of this hypothesis [18]. Fibrotic changes that take place in the walls
of the uterine arterial muscle further accent physiologic changes that would account for alterations in local blood flow [19]. Finally, approximately half of spontaneously aborted pregnancies are chromosomally normal, which infers that a local endomyometrial factor may be responsible for the loss. Whether this is a primary target organ event or secondary to the inability of the aging corpus luteum to support the pregnancy remains conjectural.
5. The oocyte donation model in humans Unfortunately, it is not possible to dissociate the impact of the gamete from the influence of the local environment on the normal development of the early embryo when studying implantation, pregnancy rates, and obstetrical outcomes of women of advanced reproductive age conceiving with their own gametes. Oocyte and embryo donation to older women, using gametes obtained from younger individuals, provides an ideal opportunity to study the contribution of each of these two variables independently from each other. When provided pharmacologic hormone replacement, the endometria of menopausal women between 40 and 60 years of age demonstrate a normal histologic, ultrasonographic, and steroid receptor response [20]. As a result, high rates of embryo implantation and pregnancy occur in women of advanced reproductive age undergoing oocyte donation (Table 2) [21]. Rates are three times higher for recipients of donated oocytes
224
M.V. Sauer / Maturitas 30 (1998) 221–225
Table 3 Results of the transfer of fertilized donor ova in women aged 40 years and older with ovarian failure compared with women under 40 years old with ovarian failure and women 40 years and older undergoing standard in vitro fertilization and embryo transfer Variable
]40 DIVF
B40 DIVF
]40 std. IVF
No. recipients No. initiated cycles No. oocytes/recipients Fertilization rate (%) No. ET cycles No. Embryos/ET Implantation rate (%) Clinical pregnancy/ET (%) Delivered pregnancy/ET (%)
65 93 15.2 9 9.0 48.2 86 4.4 9 1.0 19.7 34/86 (39.5) 29/86 (33.7)
35 46 15.3 9 6.8 62.0** 43 4.7 9 0.7 15.9 14/43 (30.2) 13/43 (30.2)
57 79 6.7 9 4.1* 39.2 70 2.9 9 1.2* 4.8* 8/70 (8.6) 6/70 (8.6)
ET, embryo transfer. Modified from J Am Med Assoc 268:1275–1279, 1992. *PB0.05 comparing women 40 years of age and older undergoing standard IVF with either group undergoing oocyte donation. **PB0.05 comparing women under 40 years of age undergoing oocyte donation with either group of women 40 years of age and older. Table 4 Results of 250 consecutive embryo transfers following oocyte donation to perimenopausal and menopausal women (ages 45–59 years) No. aspirations No. cycles without fertilization No. embryo transfers (ET) No. pregnancies per ET Preclinical abortions Clinical abortions Delivered per ET Implantation rate per embryo transferred
256 6 250 117 (46.8%) 17 12 88 (35.2%) 17.1%
ET, transcervical embryo transfer. Modified from Hum Reprod 11:2540–2543, 1996.
compared to the older population using their own gametes (Table 3) [16]. Obstetrical outcomes are also favorable, and miscarriage rates significantly reduced from the rate normally seen in older mothers [22]. The combined effect of higher implantation rates and lower miscarriage rates has made this method the preferred alternative for treating infertility in perimenopausal women and the only viable option for women seeking care after menopause (Table 4).
6. Conclusion Numerous reports continue to document the
efficacy of using oocyte donation to treat age-related infertility [23]. Similar success rates for pregnancy may be seen in women over the age of 50 years and recipients of younger age. These findings suggest that the uterus maintains its ability to produce a receptive endometrium if the patient is provided sex steroid replacement. References [1] Maroulis GB. Effect of aging on fertility and pregnancy. Semin Reprod Endocrinol 1991;9:165 – 75. [2] Ayme S, Lippman-Hand A. Maternal age effect in aneuploidy: does altered embryonic selection play a role? Am J Hum Genet 1982;34:558 – 65. [3] Plachot M. The human oocyte. Genetic aspects. Ann Genet 1997;40(2):115– 20. [4] Benzacken B, Martin-Pont B, Bergere M, Hugues JN, Wolf JP, Selva J. Chromosome 21 detection in human oocyte fluorescence in situ hybridization: possible effect of maternal age. J Asst Reprod Genet 1998;15:105 – 10. [5] Lauritsen JG. Aetiology of spontaneous abortions. A cytogenetic and epidemiologic study of 288 abortuses and their parents. Acta Obstet Gynecol Scand 1976;52:1 – 12. [6] Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine. Assisted reproductive technology in the United States and Canada: 1995 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 1998;69:389 – 398. [7] Richardson SJ, Senikas V, Nelson JF. Follicular-accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65:1231 – 7.
M.V. Sauer / Maturitas 30 (1998) 221–225 [8] Block E. Quantitative morphological investigations of the follicular system in women. Variations at different ages. Acta Anat (Basel) 1952;14:108–23. [9] Baker TG. A quantitative and cytological study of germ cells of human ovaries. Proc Roy Soc Lond (Biol) 1963;158:417 – 33. [10] Harman SM, Talbert GB. The effect of maternal age on ovulation, corpora lutea of pregnancy and implantation failure in mice. J Reprod Fertil 1970;23:33–9. [11] Holinka CF, Yueh-Chu T, Caleb EF. Reproductive aging in C57B2/6J mice; plasma progesterone, viable embryos and resorption frequency throughout pregnancy. Biol Reprod 1979;20:1201 – 11. [12] Thorneycroft IH, Soderwall AL. The nature of the litter size loss in senescent hamster. Anat Rec 1969;165:343. [13] Werner MA, Barnhard J, Gordon JW. The effects of aging on sperm and oocytes. Semin Reprod Endocrinol 1991;9:231 – 40. [14] Levran D, Ben-Shlomo I, Dor J, Ben-Rafael Z, Nebel L, Mashiach S. Aging of endometrium and oocytes: observations on conception and abortion rates in an egg donation model. Fertil Steril 1991;56:1091–4. [15] Stolwijk AM, Zielhuis GA, Sauer MV, Hamilton CJCM, Paulson RJ. The impact of the woman’s age on the success of standard and donor in-vitro fertilization. Fertil Steril 1997;67:702 – 10. [16] Sauer MV, Paulson RJ, Lobo RA. Reversing the natural decline in human fertility. An extended clinical trial of oocyte donation to women of advanced reproductive age. J Am Med Assoc 1992;268:1275–9.
.
225
[17] de Ziegler D, Bessis R, Frydman R. Vascular resistance of uterine arteries: physiological effects of estradiol and progesterone. Fertil Steril 1991;55:755 – 9. [18] Perrot-Applanat M, Groyer-Picart MT, Garcia E, Lorenzo F, Milgram E. Immunocytochemical demonstration of estrogen and progesterone receptors in muscle cells of uterine arteries in rabbits and humans. Endocrinology 1988;123:1511– 9. [19] Crawford BS, Davis J, Harrigill K. Uterine artery atherosclerotic disease: histologic features and clinical correlation. Obstet Gynecol 1997;90:210 – 5. [20] Sauer MV, Miles RA, Damoush L, Paulson RJ, Press M, Moyer D. Evaluating the effect of age on endometrial responsiveness to hormone replacement therapy: a histologic, ultrasonographic, and tissue receptor analysis. J Assist Reprod Genet 1993;10:47 – 52. [21] Sauer MV, Paulson RJ, Ary BA, Lobo RA. Three hundred cycles of oocyte donation at the University of Southern California: assessing the effect of age and diagnosis on pregnancy and implantation rates. J Assist Reprod Genet 1994;11:92 – 6. [22] Sauer MV, Paulson RJ, Lobo RA. Oocyte donation to women of advanced reproductive age: results and obstetrical outcomes in patients 45 years and older. Hum Reprod 1996;11:2540 – 3. [23] Sauer MV. Treating women of advanced reproductive age. In: Sauer MV, editor. Principles of Oocyte and Embryo Donation. New York: Springer-Verlag, 1998:271 – 92.
The impact of age on reproductive potential: lessons learned from oocyte donation Mark V. Sauer * Professor and Chief, Di6ision of Reproducti6e Endocrinology and Infertility, Department of Obstetrics and Gynaecology, College of Physicians and Surgeons, Columbia Uni6ersity, New York, NY, USA
Abstract Objecti6e: Oocyte donation allows a unique opportunity to separately study the effect of aging on uterine receptivity and oocyte quality. The purpose of this report is to review the published experience on reproductive aging in both laboratory animals and humans as it pertains to oocyte and embryo donation. Methods: A review of the published medical literature. Results: Natural fertility rates decline in most animals with age, becoming dramatically apparent in women as they enter the fifth decade of life. By the time of the perimenopause, pregnancy rarely occurs, whether or not assisted reproductive techniques are initiated. However, if oocytes are donated by young women to older women, both embryo implantation and pregnancy rates are restored to normal levels in recipients. Conclusions: These results strongly suggest the pregnancy wastage experienced by older women is largely a result of degenerative changes within the aging oocyte, rather than senescent changes in the uterus. The poor prognosis for fertility in older women can be reversed through oocyte donation from younger individuals. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Oocyte donation; Perimenopause; Advanced maternal age; Implantation
1. Introduction Fecundability rates vary among populations as a result of cultural, religious, and sexual practices. Typically, women conceive and deliver while in their twenties, with most conceptions occurring * Corresponding author. Columbia Presbyterian Medical Center, 622 West 168th Street, PH16-28, New York, NY, 10032-3784. USA. Tel.: +1 212 3059175; fax: + 1 212 3053869.
within the first six months of unprotected intercourse. Fertility rates begin to fall during the fourth decade of life and reach a nadir after the age of 40 years [1]. Further complicating the decreasing fertility rate is an alarming rise in aneuploidy in the concepti of aging females. This exaggerates the miscarriage rate and increases the number of observed anomalies in delivered offspring. For example, at age 25 years the risk of a spontaneous abortion following the clinical diagnosis of preg-
0378-5122/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0378-5122(98)00077-2
M.V. Sauer / Maturitas 30 (1998) 221–225
222
Table 1 Results of in-vitro fertilization procedures by age as reported to the National Registry of the American Society for Reproductive Medicine Age patients (years)
Retrievals
Canceled (%)
No. pregnancies
Deliveries/retrieval (%)
B35 35–39 \39
11 949 9317 4096
11.8 17.7 25.2
3826 2559 686
27.5 21.6 10.6
Modified from Fertil Steril 69: 389–398, 1998.
nancy is approximately 10% [2]. By 45 years of age, nearly half of all clinical pregnancies end in miscarriage. Pregnancy wastage is likely a result of spontaneous mutations in resting oocytes. Close to 50% of ova karyotyped in women over the age of 35 years undergoing in vitro fertilization are aneuploid [3]. Similarly, cytogenetic studies of metaphase II oocytes using FISH detect a high rate of disomy for chromosome 21 in women over the age of 40 years [4]. Likewise, a high percentage of abortuses of older mothers are chromosomally abnormal [5]. Thus, preand post-implantation losses protect the species from unwanted genetic mutations and may be thought of as natural selection against gross anomalies. Generally, women over the age of 40 years seeking fertility care have limited success. Reviewing the annual statistics for cases reported in the USA to the National IVF-ET Registry, low birth rates are noted (Table 1) [6]. However, these published statistics actually overestimate success, since many women initially enter treatment and are dropped from therapy due to a poor response to controlled ovarian hyperstimulation.
2. Ovarian age and reproduction It appears evolution precludes most women from reproducing after the age of 40 years. Certainly by age 50 years the majority of women experience menopause and the complete cessation of ovulatory function. Unlike other mammals, the ovaries in humans have nearly exhausted their supply of oocytes by the time menopause occurs [7]. Yet, fewer than 0.001% of the ovary’s original
complement of oocytes are ever ovulated. Most oocytes undergo apoptosis and atresia, which is the process by which oocytes and their follicles are removed. Histologic studies indicate that at the time of menopause, regardless of the chronologic age of the individual, at most only a few thousand eggs are left [8]. Despite the compensatory rise in stimulating pituitary gonadotropin, this cohort is unlikely to be recruited. Cadaver studies note a decline in follicular mass with advancing age and insinuate that accelerated rates of follicular atresia occur during the last decade of reproductive life before menopause. Interestingly, the largest turnover of oocytes occurs before birth. A steady decline from approximately 7 million oocytes at 20 weeks gestation, to around 2 million at the time of delivery is reported [9]. By menarche only 300000 eggs are estimated to remain, and by menopause women have virtually no primordial follicles remaining [7].
3. Animal models for reproductive aging The uteri of laboratory animals undergo age-related changes that accompany a fall in implantation and pregnancy rates. Older animals eventually are unable to achieve pregnancy despite the transfer of embryos from younger animals [10]. Similarly, in other studies older mice have been noted to have fewer implantation sites, and are twice as likely to resorb an early pregnancy compared to younger animals [11]. Correlates using other rodent models also exist, including a reduction in litter size in the aging hamster [12].
M.V. Sauer / Maturitas 30 (1998) 221–225
223
Table 2 Success rates for functionally agonadal women of various ages given hormone replacement therapy and transferred embryos following oocyte donation Age group (years)
No. cases performed
Implant. rate (%)
Resorption rate (%)
Del PR (%)
Cum PR (%)
B30 30–39 40–49 50–59
13 89 177 21
11.1 15.1 15.2 17.9
33.3 30.5 45.4 31.6
32.0 31.3 29.5 37.5
50.0 47.5 52.3 55.6
Implant. rate, implantation rate/embryo transferred; resorption rate, number of implanted embryos that spontaneously resorbed prior to delivery; del PR, delivery rate/embryo transfer performed; cum PR, cumulative pregnancy rate/patient group over time. Modified from J Asst Reprod Genet 11:92–96, 1994.
Many possible factors influence the relationship between the early conceptus and the endometrial environment. These include the rate and normal pattern of development of ova in the older female reproductive tract, delayed uterine sensitivity to blastocyst implantation secondary to a decreased capacity of older uterine tissue to take up steroids, and the less efficient uterine response to a decidualizing stimulus as seen in the mouse, rat, and hamster [13]. Thus, in rodents, an age-related decline in fertility as the result of a ‘uterine factor’ appears to exist, as evidenced by implantation failure leading to infertility and prenatal mortality.
4. Uterine aging and human reproduction It is suggested that the age-related decline in human fertility is partly due to a ‘uterine factor’ [14]. Uterine receptivity may be measured by comparing embryo implantation rates in humans of various ages undergoing in vitro fertilization and embryo transfer. Women under the age of 30 years approach rates as favorable as 20%/embryo transferred, decreasing to B10% in women 36 years of age and older [15]. After the age of 40 years, individual embryo implantation rates are but 5% [16]. Uterine blood flow decreases with declining levels of estradiol, as naturally occurs with menopause, which may adversely affect the local endometrial environment [17]. The identification of estrogen receptors in the wall of human uterine arteries is supportive of this hypothesis [18]. Fibrotic changes that take place in the walls
of the uterine arterial muscle further accent physiologic changes that would account for alterations in local blood flow [19]. Finally, approximately half of spontaneously aborted pregnancies are chromosomally normal, which infers that a local endomyometrial factor may be responsible for the loss. Whether this is a primary target organ event or secondary to the inability of the aging corpus luteum to support the pregnancy remains conjectural.
5. The oocyte donation model in humans Unfortunately, it is not possible to dissociate the impact of the gamete from the influence of the local environment on the normal development of the early embryo when studying implantation, pregnancy rates, and obstetrical outcomes of women of advanced reproductive age conceiving with their own gametes. Oocyte and embryo donation to older women, using gametes obtained from younger individuals, provides an ideal opportunity to study the contribution of each of these two variables independently from each other. When provided pharmacologic hormone replacement, the endometria of menopausal women between 40 and 60 years of age demonstrate a normal histologic, ultrasonographic, and steroid receptor response [20]. As a result, high rates of embryo implantation and pregnancy occur in women of advanced reproductive age undergoing oocyte donation (Table 2) [21]. Rates are three times higher for recipients of donated oocytes
224
M.V. Sauer / Maturitas 30 (1998) 221–225
Table 3 Results of the transfer of fertilized donor ova in women aged 40 years and older with ovarian failure compared with women under 40 years old with ovarian failure and women 40 years and older undergoing standard in vitro fertilization and embryo transfer Variable
]40 DIVF
B40 DIVF
]40 std. IVF
No. recipients No. initiated cycles No. oocytes/recipients Fertilization rate (%) No. ET cycles No. Embryos/ET Implantation rate (%) Clinical pregnancy/ET (%) Delivered pregnancy/ET (%)
65 93 15.2 9 9.0 48.2 86 4.4 9 1.0 19.7 34/86 (39.5) 29/86 (33.7)
35 46 15.3 9 6.8 62.0** 43 4.7 9 0.7 15.9 14/43 (30.2) 13/43 (30.2)
57 79 6.7 9 4.1* 39.2 70 2.9 9 1.2* 4.8* 8/70 (8.6) 6/70 (8.6)
ET, embryo transfer. Modified from J Am Med Assoc 268:1275–1279, 1992. *PB0.05 comparing women 40 years of age and older undergoing standard IVF with either group undergoing oocyte donation. **PB0.05 comparing women under 40 years of age undergoing oocyte donation with either group of women 40 years of age and older. Table 4 Results of 250 consecutive embryo transfers following oocyte donation to perimenopausal and menopausal women (ages 45–59 years) No. aspirations No. cycles without fertilization No. embryo transfers (ET) No. pregnancies per ET Preclinical abortions Clinical abortions Delivered per ET Implantation rate per embryo transferred
256 6 250 117 (46.8%) 17 12 88 (35.2%) 17.1%
ET, transcervical embryo transfer. Modified from Hum Reprod 11:2540–2543, 1996.
compared to the older population using their own gametes (Table 3) [16]. Obstetrical outcomes are also favorable, and miscarriage rates significantly reduced from the rate normally seen in older mothers [22]. The combined effect of higher implantation rates and lower miscarriage rates has made this method the preferred alternative for treating infertility in perimenopausal women and the only viable option for women seeking care after menopause (Table 4).
6. Conclusion Numerous reports continue to document the
efficacy of using oocyte donation to treat age-related infertility [23]. Similar success rates for pregnancy may be seen in women over the age of 50 years and recipients of younger age. These findings suggest that the uterus maintains its ability to produce a receptive endometrium if the patient is provided sex steroid replacement. References [1] Maroulis GB. Effect of aging on fertility and pregnancy. Semin Reprod Endocrinol 1991;9:165 – 75. [2] Ayme S, Lippman-Hand A. Maternal age effect in aneuploidy: does altered embryonic selection play a role? Am J Hum Genet 1982;34:558 – 65. [3] Plachot M. The human oocyte. Genetic aspects. Ann Genet 1997;40(2):115– 20. [4] Benzacken B, Martin-Pont B, Bergere M, Hugues JN, Wolf JP, Selva J. Chromosome 21 detection in human oocyte fluorescence in situ hybridization: possible effect of maternal age. J Asst Reprod Genet 1998;15:105 – 10. [5] Lauritsen JG. Aetiology of spontaneous abortions. A cytogenetic and epidemiologic study of 288 abortuses and their parents. Acta Obstet Gynecol Scand 1976;52:1 – 12. [6] Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine. Assisted reproductive technology in the United States and Canada: 1995 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 1998;69:389 – 398. [7] Richardson SJ, Senikas V, Nelson JF. Follicular-accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65:1231 – 7.
M.V. Sauer / Maturitas 30 (1998) 221–225 [8] Block E. Quantitative morphological investigations of the follicular system in women. Variations at different ages. Acta Anat (Basel) 1952;14:108–23. [9] Baker TG. A quantitative and cytological study of germ cells of human ovaries. Proc Roy Soc Lond (Biol) 1963;158:417 – 33. [10] Harman SM, Talbert GB. The effect of maternal age on ovulation, corpora lutea of pregnancy and implantation failure in mice. J Reprod Fertil 1970;23:33–9. [11] Holinka CF, Yueh-Chu T, Caleb EF. Reproductive aging in C57B2/6J mice; plasma progesterone, viable embryos and resorption frequency throughout pregnancy. Biol Reprod 1979;20:1201 – 11. [12] Thorneycroft IH, Soderwall AL. The nature of the litter size loss in senescent hamster. Anat Rec 1969;165:343. [13] Werner MA, Barnhard J, Gordon JW. The effects of aging on sperm and oocytes. Semin Reprod Endocrinol 1991;9:231 – 40. [14] Levran D, Ben-Shlomo I, Dor J, Ben-Rafael Z, Nebel L, Mashiach S. Aging of endometrium and oocytes: observations on conception and abortion rates in an egg donation model. Fertil Steril 1991;56:1091–4. [15] Stolwijk AM, Zielhuis GA, Sauer MV, Hamilton CJCM, Paulson RJ. The impact of the woman’s age on the success of standard and donor in-vitro fertilization. Fertil Steril 1997;67:702 – 10. [16] Sauer MV, Paulson RJ, Lobo RA. Reversing the natural decline in human fertility. An extended clinical trial of oocyte donation to women of advanced reproductive age. J Am Med Assoc 1992;268:1275–9.
.
225
[17] de Ziegler D, Bessis R, Frydman R. Vascular resistance of uterine arteries: physiological effects of estradiol and progesterone. Fertil Steril 1991;55:755 – 9. [18] Perrot-Applanat M, Groyer-Picart MT, Garcia E, Lorenzo F, Milgram E. Immunocytochemical demonstration of estrogen and progesterone receptors in muscle cells of uterine arteries in rabbits and humans. Endocrinology 1988;123:1511– 9. [19] Crawford BS, Davis J, Harrigill K. Uterine artery atherosclerotic disease: histologic features and clinical correlation. Obstet Gynecol 1997;90:210 – 5. [20] Sauer MV, Miles RA, Damoush L, Paulson RJ, Press M, Moyer D. Evaluating the effect of age on endometrial responsiveness to hormone replacement therapy: a histologic, ultrasonographic, and tissue receptor analysis. J Assist Reprod Genet 1993;10:47 – 52. [21] Sauer MV, Paulson RJ, Ary BA, Lobo RA. Three hundred cycles of oocyte donation at the University of Southern California: assessing the effect of age and diagnosis on pregnancy and implantation rates. J Assist Reprod Genet 1994;11:92 – 6. [22] Sauer MV, Paulson RJ, Lobo RA. Oocyte donation to women of advanced reproductive age: results and obstetrical outcomes in patients 45 years and older. Hum Reprod 1996;11:2540 – 3. [23] Sauer MV. Treating women of advanced reproductive age. In: Sauer MV, editor. Principles of Oocyte and Embryo Donation. New York: Springer-Verlag, 1998:271 – 92.