1375
Poor oocyte quality rather than implantation failure a cause of age-related decline in female fertility
Female fertility declines with advancing age. To establish whether this age-related reproductive failure results from diminished oocyte quality or
uterine/endometrial inadequacy ovum donation
we
in 35 infertile women,
older
oocytes from the same induced cohort. Rates for clinical pregnancy and delivery did not differ between donors (33% and 23%) and recipients (40% and 30%). Our data suggest that the age-related decline in female fertility is attributable to oocyte quality and is correctable by ovum donation. The uterus can
have designed a prospective study of women over 40 years with normal cycles who have consistently failed to conceive after ovulation induction with their own oocytes.
investigated aged 40 years
(mean 42·7 [SE 0·3]) who had failed at at attempts conception with their own (self) oocytes. Oocytes were donated by 29 young individuals (mean age 33·4 [0·7]) undergoing in-vitro fertilisation (IVF). 8 (5·3%) pregnancies were achieved in 150 cycles of ovulation induction with self-oocytes and 2 (3·3%) in 60 such cycles by in-vitro fertilisation (IVF), but none attained viability. By contrast in 50 cycles with donated oocytes 28 (56%) pregnancies and 15 (30%) deliveries were realised (p < 0·005). The rate of implantation per embryo transferred was higher (14·7%) with donated oocytes than that with self-oocytes (3·3%) (p < 0·01). To further elucidate the contribution of age to reproductive outcome, pregnancy results were compared between the young donors and older recipients. Both donors and recipients shared or
adequately sustain pregnancies even potential is artificially prolonged
when reproductive into the late 40s.
Introduction
Fertility in women is known to decline after the age of 30 years- strikingly so after 351-and fecundity is all but lost by the age of 45.2,3 This age-related decline in fertility is the result of several factors that contribute
to
overall
reproductive failure. Women over 35 require a longer period to achieve conception than younger individuals, and a
higher percentage of older than younger women will never achieve pregnancy.1 In addition, the rate of early pregnancy wastage increases substantially during the 30s and is over 50% after age 40.2 Such reproductive failure might result from either an inadequate endometrium or poor oocyte
quality. We have used ovum donation by young women to elucidate the relative contribution of oocytes and endometrium to reproductive outcome in women over 40. In this model oocyte and endometrial maturation are separate: follicular recruitment and oocyte maturation take place in young oocyte donors, whereas endometrial maturation is artificially manipulated in the recipients. We
as
Patients and methods 35 women aged 40 years or more, with normal cycles and at least 3 years of infertility, were assigned for ovum donation. All patients entered the study after complete work-up and appropriate treatment for their infertility.’’ Patients with uncorrectable tubal disease (n = 18) or endometriosis (7) underwent in-vitro fertilisation (IVF). Others with unexplained infertility (10) had IVF after failure to conceive on ovulation induction with human menopausal gonadotropins (hMG). In all patients luteal phase deficiency was ruled out by timed endometrial biopsy. Patients whose partners were infertile were exluded. Criteria for normal semen analysis were semen volume 2 ml or more and spermatozoan concentration 20 x 106/ml or more, progressive mobility 40% or more, and 40% or more normal morphology.s All ovum recipients had artificial endometrial cycles induced by sequential oestrogen 0.2-0.4 mg/day, (’Estraderm’, CIBA Pharm, Summit, NJ), and
mg/day intramuscularly, Carter-Glogan Laboratories, Phoenix, AZ).6,77 All prospective recipients underwent at least one preparatory cycle to assess the adequacy of stimulation for each individual. During these cycles, serial serum progesterone (50-150
oestradiol (E2) and progesterone (P4) measurements and endometrial biopsy was done. In-phase endometrial biopsy was a prerequisite to initiation of the treatment cycle. 12 patients whose spontaneous cycles were not suppressed by oestrogen supplementation had daily gonadotropin releasing hormone
(GnRH) agonist treatment (’Lupron’,
1 mg
subcutaneously/day)
until E2 concentrations were less than 25 pg/ml. GnRH agonist administration continued until progesterone was initiated. Ovum donors were IVF patients aged 35 years or under (n = 29) who anonymously donated excess oocytes. Of the 29 donors 17 had tubal infertility, 5 endometriosis, and 7 unexplained infertility. A predetermined number of oocytes was allocated to the donor, and the remainder to the recipient. Preovulatory oocytes only were used and no other attempt at oocyte selection was made. Between 6 and 28 oocytes were retained by the donor and 4-18 were donated to recipients. Recipients of oocytes contributed to the medical expenses of the donors. All donors were screened according to the guidelines of the American Fertility Society.8 The donors had controlled ovarian hyperstimulation by either a high dose of hMG stimulation or concomitant menotropins and a GnRH agonist.9,10 Ovum retrieval, insemination, culture, and embryo transfer were done as previously described.*’’" Embryos were morphologically graded at the time of transfer on a scale of 1-5, grade 1 being optimum and grade 5 least favourable. Serum E2 and P were measured in duplicate by commercially available radioimmunoassays (RIA) (Pantex Corp, Santa Barbara, CA). Interassay and intra-assay coefficients of variation for the E2 assay were 51% and 4-2% and for the P4 assay 66% and 5-9%, respectively. Serum &bgr;-human chorionic gonadotropin (hCG) was measured by RIA (’Tendem E hCG’, Hybritech, San Diego, CA)
Department of Science, Reproductive Endocrinology, Mount Sinai 10029, USA (D. Navot, MD, R. A.
ADDRESS:
Obstetrics, Gynecology, and Division of Reproductive Medical Center, New York, NY Bergh, MD, M. A. Williams, RNC, G. J.
Garrisi, PhD, I. Guzman, RNC, B. Sandler, MD, L. Grunfeld, MD).
Correspondence to
Dr Daniel Navot.
1376
TABLE I-COMPARISON OF INDICES IN SAME WOMEN UNDERGOING OVULATION INDUCTION, IN-VITRO FERTILISATION (IVF), AND OOCYTE DONATION
TABLE III-PREGNANCY OUTCOME IN 50 CYCLES RECIPIENTS AND 39 CYCLES OF DONORS, WITH OOCYTES FROM THE SAME COHORT
*% for recipients based on 225 embryos transferred, and for donors on 179 embryos transferred. t% of pregnancies and delivenes calculated on basis of 50 cycles for recipients and 39 for donors &Dag er;p < 005, donors vs recipients i
*Mean
(confidence intervals, CI) ‡p < 0 005. § p < 0 01
i
shown. t
Implantation, %
AUC=area under curve, hMG human menopausal
based
donors. To
on no
of cycles
gonadotropin
with a lower limit of detection at 2-5 IU/1, and with 6-8% and 6-9% interassay and intra-assay coefficients of variation. For statistical analysis, Fisher’s exact test or Student’s t-test were applied as appropriate. The level of significance was set at p < 0-05. Donors and recipients signed detailed consent forms approved by the institutional review board and its ethics subcommittee. All recipients had cardiovascular risk assessment before the pregnancy attempt.
Results donated during 50 recipient cycles. The recipients was 42-7 (SEM 0-3) years and of Duration of donors was 33-4 (0-7) years (p
Poor oocyte quality rather than implantation failure a cause of age-related decline in female fertility
Female fertility declines with advancing age. To establish whether this age-related reproductive failure results from diminished oocyte quality or
uterine/endometrial inadequacy ovum donation
we
in 35 infertile women,
older
oocytes from the same induced cohort. Rates for clinical pregnancy and delivery did not differ between donors (33% and 23%) and recipients (40% and 30%). Our data suggest that the age-related decline in female fertility is attributable to oocyte quality and is correctable by ovum donation. The uterus can
have designed a prospective study of women over 40 years with normal cycles who have consistently failed to conceive after ovulation induction with their own oocytes.
investigated aged 40 years
(mean 42·7 [SE 0·3]) who had failed at at attempts conception with their own (self) oocytes. Oocytes were donated by 29 young individuals (mean age 33·4 [0·7]) undergoing in-vitro fertilisation (IVF). 8 (5·3%) pregnancies were achieved in 150 cycles of ovulation induction with self-oocytes and 2 (3·3%) in 60 such cycles by in-vitro fertilisation (IVF), but none attained viability. By contrast in 50 cycles with donated oocytes 28 (56%) pregnancies and 15 (30%) deliveries were realised (p < 0·005). The rate of implantation per embryo transferred was higher (14·7%) with donated oocytes than that with self-oocytes (3·3%) (p < 0·01). To further elucidate the contribution of age to reproductive outcome, pregnancy results were compared between the young donors and older recipients. Both donors and recipients shared or
adequately sustain pregnancies even potential is artificially prolonged
when reproductive into the late 40s.
Introduction
Fertility in women is known to decline after the age of 30 years- strikingly so after 351-and fecundity is all but lost by the age of 45.2,3 This age-related decline in fertility is the result of several factors that contribute
to
overall
reproductive failure. Women over 35 require a longer period to achieve conception than younger individuals, and a
higher percentage of older than younger women will never achieve pregnancy.1 In addition, the rate of early pregnancy wastage increases substantially during the 30s and is over 50% after age 40.2 Such reproductive failure might result from either an inadequate endometrium or poor oocyte
quality. We have used ovum donation by young women to elucidate the relative contribution of oocytes and endometrium to reproductive outcome in women over 40. In this model oocyte and endometrial maturation are separate: follicular recruitment and oocyte maturation take place in young oocyte donors, whereas endometrial maturation is artificially manipulated in the recipients. We
as
Patients and methods 35 women aged 40 years or more, with normal cycles and at least 3 years of infertility, were assigned for ovum donation. All patients entered the study after complete work-up and appropriate treatment for their infertility.’’ Patients with uncorrectable tubal disease (n = 18) or endometriosis (7) underwent in-vitro fertilisation (IVF). Others with unexplained infertility (10) had IVF after failure to conceive on ovulation induction with human menopausal gonadotropins (hMG). In all patients luteal phase deficiency was ruled out by timed endometrial biopsy. Patients whose partners were infertile were exluded. Criteria for normal semen analysis were semen volume 2 ml or more and spermatozoan concentration 20 x 106/ml or more, progressive mobility 40% or more, and 40% or more normal morphology.s All ovum recipients had artificial endometrial cycles induced by sequential oestrogen 0.2-0.4 mg/day, (’Estraderm’, CIBA Pharm, Summit, NJ), and
mg/day intramuscularly, Carter-Glogan Laboratories, Phoenix, AZ).6,77 All prospective recipients underwent at least one preparatory cycle to assess the adequacy of stimulation for each individual. During these cycles, serial serum progesterone (50-150
oestradiol (E2) and progesterone (P4) measurements and endometrial biopsy was done. In-phase endometrial biopsy was a prerequisite to initiation of the treatment cycle. 12 patients whose spontaneous cycles were not suppressed by oestrogen supplementation had daily gonadotropin releasing hormone
(GnRH) agonist treatment (’Lupron’,
1 mg
subcutaneously/day)
until E2 concentrations were less than 25 pg/ml. GnRH agonist administration continued until progesterone was initiated. Ovum donors were IVF patients aged 35 years or under (n = 29) who anonymously donated excess oocytes. Of the 29 donors 17 had tubal infertility, 5 endometriosis, and 7 unexplained infertility. A predetermined number of oocytes was allocated to the donor, and the remainder to the recipient. Preovulatory oocytes only were used and no other attempt at oocyte selection was made. Between 6 and 28 oocytes were retained by the donor and 4-18 were donated to recipients. Recipients of oocytes contributed to the medical expenses of the donors. All donors were screened according to the guidelines of the American Fertility Society.8 The donors had controlled ovarian hyperstimulation by either a high dose of hMG stimulation or concomitant menotropins and a GnRH agonist.9,10 Ovum retrieval, insemination, culture, and embryo transfer were done as previously described.*’’" Embryos were morphologically graded at the time of transfer on a scale of 1-5, grade 1 being optimum and grade 5 least favourable. Serum E2 and P were measured in duplicate by commercially available radioimmunoassays (RIA) (Pantex Corp, Santa Barbara, CA). Interassay and intra-assay coefficients of variation for the E2 assay were 51% and 4-2% and for the P4 assay 66% and 5-9%, respectively. Serum &bgr;-human chorionic gonadotropin (hCG) was measured by RIA (’Tendem E hCG’, Hybritech, San Diego, CA)
Department of Science, Reproductive Endocrinology, Mount Sinai 10029, USA (D. Navot, MD, R. A.
ADDRESS:
Obstetrics, Gynecology, and Division of Reproductive Medical Center, New York, NY Bergh, MD, M. A. Williams, RNC, G. J.
Garrisi, PhD, I. Guzman, RNC, B. Sandler, MD, L. Grunfeld, MD).
Correspondence to
Dr Daniel Navot.
1376
TABLE I-COMPARISON OF INDICES IN SAME WOMEN UNDERGOING OVULATION INDUCTION, IN-VITRO FERTILISATION (IVF), AND OOCYTE DONATION
TABLE III-PREGNANCY OUTCOME IN 50 CYCLES RECIPIENTS AND 39 CYCLES OF DONORS, WITH OOCYTES FROM THE SAME COHORT
*% for recipients based on 225 embryos transferred, and for donors on 179 embryos transferred. t% of pregnancies and delivenes calculated on basis of 50 cycles for recipients and 39 for donors &Dag er;p < 005, donors vs recipients i
*Mean
(confidence intervals, CI) ‡p < 0 005. § p < 0 01
i
shown. t
Implantation, %
AUC=area under curve, hMG human menopausal
based
donors. To
on no
of cycles
gonadotropin
with a lower limit of detection at 2-5 IU/1, and with 6-8% and 6-9% interassay and intra-assay coefficients of variation. For statistical analysis, Fisher’s exact test or Student’s t-test were applied as appropriate. The level of significance was set at p < 0-05. Donors and recipients signed detailed consent forms approved by the institutional review board and its ethics subcommittee. All recipients had cardiovascular risk assessment before the pregnancy attempt.
Results donated during 50 recipient cycles. The recipients was 42-7 (SEM 0-3) years and of Duration of donors was 33-4 (0-7) years (p
