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Aging of endometrium and oocytes: observations on conception and abortion rates in an egg donation model
Vol. 56, No.6, December 1991
FERTILITY AND STERILITY Copyright e
1991 The American Fertility Society
Printed on acid-free paper in U.S.A.
Aging of endometrium and oocytes: observations on conception and abortion rates in an egg donation model
David Levran, M.D.*t Izhar Ben-Shlomo, M.D.* Jehoshua Dor, M.D.*
Zion Ben-Rafael, M.D.* Laslo Nebel, M.D.* Shlomo Mashiach, M.D.*
Sheba Medical Center, Tel Haslwmer, and The Sachler Sclwol of Medicine, Tel Aviv University, Tel Aviv, Israel
Objective: To assess the comparative contribution of endometrial and oocytic aging to the decline in fertility with age. Design: Retrospective analysis of conception and abortion rates in an egg donation program, with respect to donor and recipient ages. Patients: All oocyte recipients had ovarian failure. Donors were women undergoing in vitro fertilization who contributed up to a third of retrieved oocytes. Interventions: None. Results: Thirty pregnancies (28 intrauterine) were recorded in 169 reception cycles originating from 91 donation cycles. Women who conceived were younger than those who did not (median age 31 versus 37; P < 0.046), with no difference in age of donors. There was a significant difference in spontaneous abortion rate by age of donor rather than by age of recipient. Donors to successful pregnancies were younger than donors to aborted pregnancies (median age 27.5 versus 33; P < 0.0211), but the 11 women with aborted pregnancies did not differ in age from the 17 women with successful pregnancies. Conclusions: In women, endometrial function as expressed by conception rate in the recipients declines with age, whereas it is oocyte age that primarily influences risk of abortion. Fertil Steril1991;56:1091-4
In recent years, many women have postponed childbearing, with a concomitant decline in fecundability and a higher miscarriage rate. Although this phenomenon has recently received a great deal of public attention and has particularly interested in vitro fertilization (IVF) practitioners who perform oocyte donation,1-3 the data on the relationship between postponed childbearing and the success rate of oocyte donation programs are based on a very small number of cases. The relative contribution of the various components of the reproductive system to reduced fer-
Received April 9, 1991; revised and accepted August 20, 1991.
* Department of Obstetrics and Gynecology.
t Reprint requests: David Levran, M.D., Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer 52621, Israel. :j: Department of Embryology. Vol. 56, No.6, December 1991
tility is only partially understood. 4 Chronologically, the first component that fails is the ovary. The continued responsiveness of the endometrium to estrogenic stimulus at menopause may indicate preserved reproductive potential. In several mammalian species, the endometrium undergoes marked age-related morphological and physiological5- 8 changes considered responsible, at least in part, for the decline in reproductive capacity. In humans, direct evidence of reduced reproductive capacity of the endometrium does not exist. Oocyte donation, during which women of reproductive age with essentially no ovarian function are treated with estrogen (E) and progesterone (P) before embryos are introduced to the uterine cavity, presents a unique opportunity to study the effect of aging of both endometrium and oocytes on reproduction. We present an analysis of results from our oocyte donation program that evaluated the specific conLevran et al.
Aging of endometrium and oocytes
1091
tribution of the endometrium and the oocytes to the decline of fertility with age. MATERIALS AND METHODS
In Israel, egg donation programs can use only 00cytes obtained from women who are themselves undergoing IVF. Between 1985 and 1990, 91 donation cycles were performed in our program, and embryos were transferred to 169 recipients. After obtaining an informed consent, donor women contributed up to one third of the retrieved oocytes, and oocytes from one donor could be distributed to more than one recipient. Induction of follicular growth in the donor was accomplished by a daily dose of 225 IV of luteinizing hormone and 225 IV of follicle-stimulating hormone (FSH) (human menopausal gonadotropin Pergonal; Teva, Kfar Sava, Israel), started on the 3rd day of the menstrual cycle. When at least two follicles reached 16 mm and estradiol (E 2) serum level rose >500 ng/mL, 10,000 IV of human chorionic gonadotropin (hCG) were administered. Transvaginal oocyte retrieval, guided by a 6.5MHz vaginal sector probe (Model ESI 1000, Elscint, Haifa, Israel), was performed 32 to 36 hours after hCG administration. Oocytes were suspended and inseminated in modified Earl's medium by a method described previously.9 Recipients were women of reproductive age with isolated ovarian failure. Those who had primary ovarian failure had been treated by substitution therapy so that their overall previous sex steroid exposure did not differ from that in women with secondary ovarian failure. Hormonal preparation of the recipients constituted of E2 valerate 1 mg on day 1, with subsequent daily doses rising by 1 mg/d for 6 days, followed by a maintenance dose of 2 mg/d. Progesterone 100 mg/d was started on the 2nd day of the maintenance dose. This protocol has been shown to produce a serum hormonal profile and histologic endometrial response resembling those of spontaneous ovulatory cycles. Oocytes set aside for donation were fertilized by the recipient's husband's semen. When the husband's semen was abnormal, donor semen was used. Donors and recipients were matched primarily for physical features, with no matching for age attempted. Two protocols for synchronization of recipients' endometrium, one for fresh embryos and one for frozen/thawed embryos, were used. Synchronization of the recipients of fresh embryos was based on the 6-day rule. 10 Estradiol valerate is first administered 1092
Levran et aI.
Aging of endometrium and oocytes
to the recipient on the day that the initial E2 rise is diagnosed in the donor. Our freezing protocol is as described by Lassalle et al. l l Embryos were thawed and transferred to the recipients on the 3rd day of P administration (assignment of recipients to either protocol was done randomly). We analyzed conception and miscarriage rates with respect to age of both recipients and donors. Statistical analysis used Mann-Whitney V-test, X2 test, and Fisher's exact test as appropriate.
RESULTS
Ninety-one donation cycles distributed among 169 recipients were studied. Thirty pregnancies were established in the recipients. The median number of embryos transferred did not differ between recipients who conceived and recipients who failed to conceive (2 in both groups). Donors who contributed to cycles that resulted in conception did not differ in age from those who contributed to unsuccessful cycles (median age 31 and 30.5, respectively). However, recipients who conceived were significantly younger (median age 31 years [95% confidence interval 27 to 37] versus 37 years [34 to 38]; P < 0.046) than those who did not. An alternative approach to the same data is given in Table 1. Separate analysis considering fresh versus frozen/thawed embryo transfer did not change this result. Of the 30 pregnancies reported here, 17 ended successfully, 11 ended in spontaneous abortion, and 2 were ectopic. The donors who contributed to the aborted pregnancies were significantly older than those who contributed to the successful pregnancies (median ages 33 and 27.5, respectively; P < 0.0211; Table 2 presents these results by age groups), although the age of recipients who aborted did not differ from the age of those who carried the pregnancy to successful conclusion (ectopic pregnancies excluded).
Table 1 Conception Rate by Age Among 169 Recipients in an Egg Donation Program a Age group
No conception
Conception
.,,;32 (n = 58) ~33 (n = 111)
42 97
16 (31.4)b
14 (12.6)
a
Values in parentheses are percents of total.
b
p < 0.05 (X 2 test with Yates' correction).
Fertility and Sterility
Table 2 Pregnancy Success Rate by Age of Donors in an Egg Donation Program a Age group
Successful pregnancy
Miscarriage
18)
14
(n = 10)
3
4 7
,,;;31 (n ~32 a
=
p = 0.0171 (Fisher's exact test).
DISCUSSION
Fertility declines in women well before menstruation ceases. Part of this decline of fertility is caused by inadequate follicular response to hypophyseal stimulation, which in turn leads to elevated gonadotropin levels that extend the period of menstruation before its final disappearance. This hypophyseal reaction and the preserved pattern of secretion after menopause serves as evidence of preserved function of the hypothalamic-hypophyseal axis, regardless of age. 12 Likewise, continued responsiveness of the endometrium to ovarian steroids may also reflect such a preserved capacity. This concept underlies treatment of women with ovarian failure by egg donation. Until now there was no way to estimate the functional aging of the endometrium and its contribution to the decline in fertility with age. In laboratory animals, mainly rodents, endometrial aging has been extensively studied. Morphologically, as age increases there is an increase in collagen content,5,6 a reduced number of stromal cells,4 reduced tissuedeoxyribonucleic acid content,4 and fewer E receptors on the surface of endometrial cells. 13 Functionally, there is a reduction in litter size despite adequate ovulation, 5 reduced endometrial blood flow,5 and reduced capacity to form deciduomata in response to various stimuli. 7 In an extensive study, Ohta7 demonstrated that functional aging ofrat endometrium is a primary process independent of ovarian and central nervous system activity, though intimately related to them. He further demonstrated that reproductive function is compromised before the morphological counterparts of aging are manifested. The human endometrium, while still responsive to ovarian steroids at older age, may at the same time be unable to establish and/or maintain a pregnancy. One indication of the endometrial role in reduced fertility with age is found in a report by Sterzik et al,14 who described a larger proportion of out-ofphase endometrium in women older than 35 during unsuccessful IVF cycles. This finding agrees with the results of rodent studies, discussed above. HowVol. 56, No.6, December 1991
ever, the described methodology could not distinguish between the specific contributions of the endometrium and ovaries because inadequate endometrial histology could be attributed to either or both organs. We recently have demonstrated that egg donation can serve as a model for the understanding of various aspects of human reproduction. 15 Our results in a large number of patients indicate an age-related decline in endometrial reproductive capacity. We reached this conclusion based on the following indicators: (1) hormonal therapy, aimed at achieving adequate luteal endometrium when embryos were introduced, was the same for all patients; (2) endogenous ovarian steroid production was negligible in all patients; (3) the age of oocyte donors did not differ between recipients who did and did not conceive; and (4) no male factor was involved. Thus, the embryos could be considered to have the same implantation potential, irrespective of the recipient. The finding that older recipients conceived less frequently than younger recipients reflects the importance of the endometrium to the decline in fecundability with age. The potential of oocytes to produce pregnancies has been previously shown by us to be much higher than reflected by regular pregnancy rates found in IVF programs. 15 This was also dem0nstrated by de Ziegler and Frydman,16 who reported pregnancy rates (PRs) after donation to be higher than after cryopreservation of embryos from IVF. The PR of only 12.6% in recipients age 33 or more compared with 31.4% in the younger group further reflects the importance of the endometrial age in implantation. In an egg donation program, Sauer et al. 3 achieved similar conception rates in patients over and under 40 years of age who suffered from ovarian failure and concluded that this represents preserved endometrial capacity. Most of the recipients on that program were older than the inflection age after which we found that fecundity declines significantly, which may explain the difference between their conclusion and ours. It is well recognized that miscarriage rate increases with age in both spontaneous pregnancies and pregnancies resulting from IVF .17,18 Risch et al. 2 found that the spontaneous abortion rate begins to rise at 30 years of age. Older women are likely to produce oocytes with chromosomal abnormalities, as shown by a higher rate of trisomies in children born to older women. 19 This increased rate of abnormal oocytes leads in turn to abnormal conceptus that are eventually aborted. Our finding that after implantation it is the age of the donor and not the Levran et a1.
Aging of endometrium and oocytes
1093
age of the recipient that determines the risk of abortion supports this view and suggests that the increasing abortion rate with age should be attributed mainly to aging of the oocytes rather than to the endometrium. In summary, the unique setting of an egg donation program enabled us to approach two fundamental issues affecting fertility at advanced ages. We found statistically significant evidence that the aging of the endometrium is a major determinant of reduced fecundity with age, whereas aged oocytes are major determinants of increased abortion rates found at higher ages. REFERENCES 1. Federation CECOS, Schwartz D, Mayaux MJ: Female fecundity as a function of age. N Eng\ J Med 306:404, 1~82 2. Risch HA, Weiss NS, Clarke AE, Miller AB: Risk factors for spontaneous abortion and its recurrence. Am J Epidemiol 128:420, 1988 3. Sauer MV, Paulson RJ, Lobo RA: A preliminary report on oocyte donation extending reproductive potential to women over 40. N Engl J Med 323:1157,1990 4. Wilcox AJ: Female fecundity as a function of age. (Letter) N Engl J Med 307:373, 1982 5. Craig SS, Jollie WP: Age changes in density of endometrial stromal cells of the rat. Exp Gerontol 20:93, 1985 6. Rahima A, Soderwall AL: Endometrial blood flow in pregnant young and senescent female golden hamsters. Exp Gerontol 13:47, 1978 7. Ohta Y: Age-related decline in deciduogenic ability of the rat uterus. Bioi Reprod 37:779, 1987 8. Brown C, Gosden RG, Poyser NL: Effects of age and steroid treatment on prostaglandin production by the rat uterus in relation to implantation. J Reprod Fertil 70:649, 1984
1094
Levran et al.
Aging of endometrium and oocytes
9. Rudak E, Dor J, Mashiach S, Nebel L, Goldman B: Chromosomal analysis of multipronuclear human oocytes fertilized in vitro. Fertil Steril 41:538, 1984 10. Levran D, Lopata A, Nayudu PL, Martin MJ, McBain JC, Bayly CM, Speirs AL, Johnston WIH: Analysis of the outcome of in vitro fertilization in relation to the timing of human chorionic gonadotropin administration by the duration of estradiol rise in stimulated cycles. Fertil Steril 44:335, 1985 11. Lassalle B, Testart J, Renard JP: Human embryo features that influence the success of cryopreservation with the use of 1,2 propandiol. Fertil Steril 44:645, 1985 12. Alexander SE, Aksel S, Hazelton JM, Yeoman RR, Gilmore SM: The effect of aging on hypothalamic function in oophorectomized women. Am J Obstet Gynecol 162:446, 1990 13. Han Z, Kokkonen GC, Roth GS: Effect of aging on populations of estrogen receptor-containing cells in the rat uterus. Exp Cell Res 180:234, 1989 14. Sterzik K, Dallenbach C, Schnieder V, Sasse V, DellenbachHellwag G: In vitro fertilization: the degree of endometrial insufficiency varies with the type of ovarian stimulation. Fertil Steril50:457,1988 15. Levran D, DorJ, Rudak E, Nebel L, Ben-Shlomo I, Mashiach S: Pregnancy potential of human oocytes-the effect of cryopreservation. N Engl J Med 323:1153,1990 16. de Ziegler D, Frydman R: Different implantation rates after transfers of cryopreserved embryos originating from donated oocytes or from regular in vitro fertilization. Fertil Steril 54: 682, 1990 17. Hook EB: Spontaneous death of fetuses with chromosomal abnormalities diagnosed prenatally. N Engl J Med 299:1036, 1978 18. Padilla SL, Garcia JE: Effect of maternal age and number of in vitro fertilization procedures on pregnancy outcome. Fertil Steril 52:270, 1989 19. Hook EB: Rates of chromosome abnormalities at different maternal ages. Obstet Gynecol 58:282, 1981
Fertility and Sterility
FERTILITY AND STERILITY Copyright e
1991 The American Fertility Society
Printed on acid-free paper in U.S.A.
Aging of endometrium and oocytes: observations on conception and abortion rates in an egg donation model
David Levran, M.D.*t Izhar Ben-Shlomo, M.D.* Jehoshua Dor, M.D.*
Zion Ben-Rafael, M.D.* Laslo Nebel, M.D.* Shlomo Mashiach, M.D.*
Sheba Medical Center, Tel Haslwmer, and The Sachler Sclwol of Medicine, Tel Aviv University, Tel Aviv, Israel
Objective: To assess the comparative contribution of endometrial and oocytic aging to the decline in fertility with age. Design: Retrospective analysis of conception and abortion rates in an egg donation program, with respect to donor and recipient ages. Patients: All oocyte recipients had ovarian failure. Donors were women undergoing in vitro fertilization who contributed up to a third of retrieved oocytes. Interventions: None. Results: Thirty pregnancies (28 intrauterine) were recorded in 169 reception cycles originating from 91 donation cycles. Women who conceived were younger than those who did not (median age 31 versus 37; P < 0.046), with no difference in age of donors. There was a significant difference in spontaneous abortion rate by age of donor rather than by age of recipient. Donors to successful pregnancies were younger than donors to aborted pregnancies (median age 27.5 versus 33; P < 0.0211), but the 11 women with aborted pregnancies did not differ in age from the 17 women with successful pregnancies. Conclusions: In women, endometrial function as expressed by conception rate in the recipients declines with age, whereas it is oocyte age that primarily influences risk of abortion. Fertil Steril1991;56:1091-4
In recent years, many women have postponed childbearing, with a concomitant decline in fecundability and a higher miscarriage rate. Although this phenomenon has recently received a great deal of public attention and has particularly interested in vitro fertilization (IVF) practitioners who perform oocyte donation,1-3 the data on the relationship between postponed childbearing and the success rate of oocyte donation programs are based on a very small number of cases. The relative contribution of the various components of the reproductive system to reduced fer-
Received April 9, 1991; revised and accepted August 20, 1991.
* Department of Obstetrics and Gynecology.
t Reprint requests: David Levran, M.D., Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer 52621, Israel. :j: Department of Embryology. Vol. 56, No.6, December 1991
tility is only partially understood. 4 Chronologically, the first component that fails is the ovary. The continued responsiveness of the endometrium to estrogenic stimulus at menopause may indicate preserved reproductive potential. In several mammalian species, the endometrium undergoes marked age-related morphological and physiological5- 8 changes considered responsible, at least in part, for the decline in reproductive capacity. In humans, direct evidence of reduced reproductive capacity of the endometrium does not exist. Oocyte donation, during which women of reproductive age with essentially no ovarian function are treated with estrogen (E) and progesterone (P) before embryos are introduced to the uterine cavity, presents a unique opportunity to study the effect of aging of both endometrium and oocytes on reproduction. We present an analysis of results from our oocyte donation program that evaluated the specific conLevran et al.
Aging of endometrium and oocytes
1091
tribution of the endometrium and the oocytes to the decline of fertility with age. MATERIALS AND METHODS
In Israel, egg donation programs can use only 00cytes obtained from women who are themselves undergoing IVF. Between 1985 and 1990, 91 donation cycles were performed in our program, and embryos were transferred to 169 recipients. After obtaining an informed consent, donor women contributed up to one third of the retrieved oocytes, and oocytes from one donor could be distributed to more than one recipient. Induction of follicular growth in the donor was accomplished by a daily dose of 225 IV of luteinizing hormone and 225 IV of follicle-stimulating hormone (FSH) (human menopausal gonadotropin Pergonal; Teva, Kfar Sava, Israel), started on the 3rd day of the menstrual cycle. When at least two follicles reached 16 mm and estradiol (E 2) serum level rose >500 ng/mL, 10,000 IV of human chorionic gonadotropin (hCG) were administered. Transvaginal oocyte retrieval, guided by a 6.5MHz vaginal sector probe (Model ESI 1000, Elscint, Haifa, Israel), was performed 32 to 36 hours after hCG administration. Oocytes were suspended and inseminated in modified Earl's medium by a method described previously.9 Recipients were women of reproductive age with isolated ovarian failure. Those who had primary ovarian failure had been treated by substitution therapy so that their overall previous sex steroid exposure did not differ from that in women with secondary ovarian failure. Hormonal preparation of the recipients constituted of E2 valerate 1 mg on day 1, with subsequent daily doses rising by 1 mg/d for 6 days, followed by a maintenance dose of 2 mg/d. Progesterone 100 mg/d was started on the 2nd day of the maintenance dose. This protocol has been shown to produce a serum hormonal profile and histologic endometrial response resembling those of spontaneous ovulatory cycles. Oocytes set aside for donation were fertilized by the recipient's husband's semen. When the husband's semen was abnormal, donor semen was used. Donors and recipients were matched primarily for physical features, with no matching for age attempted. Two protocols for synchronization of recipients' endometrium, one for fresh embryos and one for frozen/thawed embryos, were used. Synchronization of the recipients of fresh embryos was based on the 6-day rule. 10 Estradiol valerate is first administered 1092
Levran et aI.
Aging of endometrium and oocytes
to the recipient on the day that the initial E2 rise is diagnosed in the donor. Our freezing protocol is as described by Lassalle et al. l l Embryos were thawed and transferred to the recipients on the 3rd day of P administration (assignment of recipients to either protocol was done randomly). We analyzed conception and miscarriage rates with respect to age of both recipients and donors. Statistical analysis used Mann-Whitney V-test, X2 test, and Fisher's exact test as appropriate.
RESULTS
Ninety-one donation cycles distributed among 169 recipients were studied. Thirty pregnancies were established in the recipients. The median number of embryos transferred did not differ between recipients who conceived and recipients who failed to conceive (2 in both groups). Donors who contributed to cycles that resulted in conception did not differ in age from those who contributed to unsuccessful cycles (median age 31 and 30.5, respectively). However, recipients who conceived were significantly younger (median age 31 years [95% confidence interval 27 to 37] versus 37 years [34 to 38]; P < 0.046) than those who did not. An alternative approach to the same data is given in Table 1. Separate analysis considering fresh versus frozen/thawed embryo transfer did not change this result. Of the 30 pregnancies reported here, 17 ended successfully, 11 ended in spontaneous abortion, and 2 were ectopic. The donors who contributed to the aborted pregnancies were significantly older than those who contributed to the successful pregnancies (median ages 33 and 27.5, respectively; P < 0.0211; Table 2 presents these results by age groups), although the age of recipients who aborted did not differ from the age of those who carried the pregnancy to successful conclusion (ectopic pregnancies excluded).
Table 1 Conception Rate by Age Among 169 Recipients in an Egg Donation Program a Age group
No conception
Conception
.,,;32 (n = 58) ~33 (n = 111)
42 97
16 (31.4)b
14 (12.6)
a
Values in parentheses are percents of total.
b
p < 0.05 (X 2 test with Yates' correction).
Fertility and Sterility
Table 2 Pregnancy Success Rate by Age of Donors in an Egg Donation Program a Age group
Successful pregnancy
Miscarriage
18)
14
(n = 10)
3
4 7
,,;;31 (n ~32 a
=
p = 0.0171 (Fisher's exact test).
DISCUSSION
Fertility declines in women well before menstruation ceases. Part of this decline of fertility is caused by inadequate follicular response to hypophyseal stimulation, which in turn leads to elevated gonadotropin levels that extend the period of menstruation before its final disappearance. This hypophyseal reaction and the preserved pattern of secretion after menopause serves as evidence of preserved function of the hypothalamic-hypophyseal axis, regardless of age. 12 Likewise, continued responsiveness of the endometrium to ovarian steroids may also reflect such a preserved capacity. This concept underlies treatment of women with ovarian failure by egg donation. Until now there was no way to estimate the functional aging of the endometrium and its contribution to the decline in fertility with age. In laboratory animals, mainly rodents, endometrial aging has been extensively studied. Morphologically, as age increases there is an increase in collagen content,5,6 a reduced number of stromal cells,4 reduced tissuedeoxyribonucleic acid content,4 and fewer E receptors on the surface of endometrial cells. 13 Functionally, there is a reduction in litter size despite adequate ovulation, 5 reduced endometrial blood flow,5 and reduced capacity to form deciduomata in response to various stimuli. 7 In an extensive study, Ohta7 demonstrated that functional aging ofrat endometrium is a primary process independent of ovarian and central nervous system activity, though intimately related to them. He further demonstrated that reproductive function is compromised before the morphological counterparts of aging are manifested. The human endometrium, while still responsive to ovarian steroids at older age, may at the same time be unable to establish and/or maintain a pregnancy. One indication of the endometrial role in reduced fertility with age is found in a report by Sterzik et al,14 who described a larger proportion of out-ofphase endometrium in women older than 35 during unsuccessful IVF cycles. This finding agrees with the results of rodent studies, discussed above. HowVol. 56, No.6, December 1991
ever, the described methodology could not distinguish between the specific contributions of the endometrium and ovaries because inadequate endometrial histology could be attributed to either or both organs. We recently have demonstrated that egg donation can serve as a model for the understanding of various aspects of human reproduction. 15 Our results in a large number of patients indicate an age-related decline in endometrial reproductive capacity. We reached this conclusion based on the following indicators: (1) hormonal therapy, aimed at achieving adequate luteal endometrium when embryos were introduced, was the same for all patients; (2) endogenous ovarian steroid production was negligible in all patients; (3) the age of oocyte donors did not differ between recipients who did and did not conceive; and (4) no male factor was involved. Thus, the embryos could be considered to have the same implantation potential, irrespective of the recipient. The finding that older recipients conceived less frequently than younger recipients reflects the importance of the endometrium to the decline in fecundability with age. The potential of oocytes to produce pregnancies has been previously shown by us to be much higher than reflected by regular pregnancy rates found in IVF programs. 15 This was also dem0nstrated by de Ziegler and Frydman,16 who reported pregnancy rates (PRs) after donation to be higher than after cryopreservation of embryos from IVF. The PR of only 12.6% in recipients age 33 or more compared with 31.4% in the younger group further reflects the importance of the endometrial age in implantation. In an egg donation program, Sauer et al. 3 achieved similar conception rates in patients over and under 40 years of age who suffered from ovarian failure and concluded that this represents preserved endometrial capacity. Most of the recipients on that program were older than the inflection age after which we found that fecundity declines significantly, which may explain the difference between their conclusion and ours. It is well recognized that miscarriage rate increases with age in both spontaneous pregnancies and pregnancies resulting from IVF .17,18 Risch et al. 2 found that the spontaneous abortion rate begins to rise at 30 years of age. Older women are likely to produce oocytes with chromosomal abnormalities, as shown by a higher rate of trisomies in children born to older women. 19 This increased rate of abnormal oocytes leads in turn to abnormal conceptus that are eventually aborted. Our finding that after implantation it is the age of the donor and not the Levran et a1.
Aging of endometrium and oocytes
1093
age of the recipient that determines the risk of abortion supports this view and suggests that the increasing abortion rate with age should be attributed mainly to aging of the oocytes rather than to the endometrium. In summary, the unique setting of an egg donation program enabled us to approach two fundamental issues affecting fertility at advanced ages. We found statistically significant evidence that the aging of the endometrium is a major determinant of reduced fecundity with age, whereas aged oocytes are major determinants of increased abortion rates found at higher ages. REFERENCES 1. Federation CECOS, Schwartz D, Mayaux MJ: Female fecundity as a function of age. N Eng\ J Med 306:404, 1~82 2. Risch HA, Weiss NS, Clarke AE, Miller AB: Risk factors for spontaneous abortion and its recurrence. Am J Epidemiol 128:420, 1988 3. Sauer MV, Paulson RJ, Lobo RA: A preliminary report on oocyte donation extending reproductive potential to women over 40. N Engl J Med 323:1157,1990 4. Wilcox AJ: Female fecundity as a function of age. (Letter) N Engl J Med 307:373, 1982 5. Craig SS, Jollie WP: Age changes in density of endometrial stromal cells of the rat. Exp Gerontol 20:93, 1985 6. Rahima A, Soderwall AL: Endometrial blood flow in pregnant young and senescent female golden hamsters. Exp Gerontol 13:47, 1978 7. Ohta Y: Age-related decline in deciduogenic ability of the rat uterus. Bioi Reprod 37:779, 1987 8. Brown C, Gosden RG, Poyser NL: Effects of age and steroid treatment on prostaglandin production by the rat uterus in relation to implantation. J Reprod Fertil 70:649, 1984
1094
Levran et al.
Aging of endometrium and oocytes
9. Rudak E, Dor J, Mashiach S, Nebel L, Goldman B: Chromosomal analysis of multipronuclear human oocytes fertilized in vitro. Fertil Steril 41:538, 1984 10. Levran D, Lopata A, Nayudu PL, Martin MJ, McBain JC, Bayly CM, Speirs AL, Johnston WIH: Analysis of the outcome of in vitro fertilization in relation to the timing of human chorionic gonadotropin administration by the duration of estradiol rise in stimulated cycles. Fertil Steril 44:335, 1985 11. Lassalle B, Testart J, Renard JP: Human embryo features that influence the success of cryopreservation with the use of 1,2 propandiol. Fertil Steril 44:645, 1985 12. Alexander SE, Aksel S, Hazelton JM, Yeoman RR, Gilmore SM: The effect of aging on hypothalamic function in oophorectomized women. Am J Obstet Gynecol 162:446, 1990 13. Han Z, Kokkonen GC, Roth GS: Effect of aging on populations of estrogen receptor-containing cells in the rat uterus. Exp Cell Res 180:234, 1989 14. Sterzik K, Dallenbach C, Schnieder V, Sasse V, DellenbachHellwag G: In vitro fertilization: the degree of endometrial insufficiency varies with the type of ovarian stimulation. Fertil Steril50:457,1988 15. Levran D, DorJ, Rudak E, Nebel L, Ben-Shlomo I, Mashiach S: Pregnancy potential of human oocytes-the effect of cryopreservation. N Engl J Med 323:1153,1990 16. de Ziegler D, Frydman R: Different implantation rates after transfers of cryopreserved embryos originating from donated oocytes or from regular in vitro fertilization. Fertil Steril 54: 682, 1990 17. Hook EB: Spontaneous death of fetuses with chromosomal abnormalities diagnosed prenatally. N Engl J Med 299:1036, 1978 18. Padilla SL, Garcia JE: Effect of maternal age and number of in vitro fertilization procedures on pregnancy outcome. Fertil Steril 52:270, 1989 19. Hook EB: Rates of chromosome abnormalities at different maternal ages. Obstet Gynecol 58:282, 1981
Fertility and Sterility