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The effect of progesterone supplementation around the time of oocyte recovery in patients superovulated for in vitro fertilization
FERTILITY AND STERILITY Copyright c 1986 The American Fertility Society
Vol. 45, No. 4, April 1986 Printed in U.S -4. .
The effect of progesterone supplementation around the time of oocyte recovery in patients superovulated for in vitro fertilization
Alan Trounson, Ph.D.* Donna Howlett, B.Sc. Peter Rogers, Ph.D. Hans-Otto Hoppen, Ph.D. Centre for Early Human Development and Department of Obstetrics and Gynaecology, Monash University, Queen Victoria Medical Centre, Melbourne, Victoria, Australia
A randomized control trial involving 42 superovulated in vitro fertilization (IVF) patients was carried out to investigate the effects of providing supplementary progesterone (P) around the time of laparoscopy. P was given 12 to 15 hours and 1 hour before and 24 hours after laparoscopy in one group (group B); human chorionic gonadotropin was given 12 hours before laparoscopy in another group (group C); and the remainder received no treatment in addition to normal IVF procedures (group A). There was no difference in fertilization rate, the proportion of normally developing embryos, pregnancy rate, or birth rate between the treatment groups. We conclude that in the superovulation schedule used, P supplementation around the time qf laparoscopy does not affect success rate of IVF. Fertil Steril45:532, 1986
The hormonal profiles of conception cycles are characterized by sustained luteal progesterone (P) secretion, although the range of peripheral concentrations of P compatible with pregnancy is not well defined, despite several well-planned studies. 1 • 2 In the study reported by Lenton et al., 2 P concentrations were higher in the conception group, particularly 3 to 8 days after the luteinizing hormone (LH) surge. Reduced P secretion and luteal dysfunction have been noted in monkeys 3 and humans 4 · 5 after follicular aspiration for oocyte recovery in the natural ovulatory cycle. In women superovulated for in vitro fertilization (IVF), plasma P levels are considerably higher than in the natural ovulatory cycle, because of multiple corpora lutea. Reduced P secretion and Received September 10, 1985; revised and accepted December 26, 1985. *Reprint requests: Dr. Alan Trounson, Centre for Early Human Development, Queen Victoria Medical Centre, 172 Lonsdale Street, Melbourne, Victoria, Australia 3000. 532
Trounson et al. Progesterone supplementation for IVF
luteal defects are not readily apparent under these circumstances. 5 • 6 However, there are some reports 7 • 8 that patients superovulated with human menopausal gonadotropin (hMG), with higher luteal phase P levels, particularly days 3 to 8 after laparoscopy, are more likely to become pregnant after embryo transfer. In our studies, we have observed a major reduction in peripheral plasma P during anesthesia and follicular aspiration for oocyte recovery, particularly in some individual patients. 9 These experiments were undertaken to investigate whether supplementation of P levels around the time of laparoscopy by the administration of exogenous P or human chorionic gonadotropin (hCG) would improve the chance of pregnancy for IVF patients. MATERIALS AND METHODS
The study was carried out with patients attending the Monash-Epworth IVF program. SuperFertility and Sterility
25 .......
E ..... Cl 20
c: ........
8
C1)
c: 0 .....
-
15
C1)
( /)
C1)
Cl 0
.....
10
a.
a!
E (/)
a!
5
ii:
0
Time (hr)
Figure 1 P levels ( ± standard error of the mean) in IVF patients around the time of laparoscopy following normal procedures (A), supplementation with exogenous P (B ), or a supplementary injection of hCG (C).
ovulation was induced with a combination of clomiphene citrate (CC; Clomid, Merrell and Company, Sydney, NSW, Australia) and hMG (Humegon, Organon, Sydney, NSW, Australia), as previously described.10-12 CC was given at a dose of 50 to 150 mg daily for 5 days, beginning 10 days before the expected mean day of the LH surge. 13 On the second day of CC administration, the patients were given 75 to 225 IU of hMG for 2 to 5 days. The hMG treatment was stopped yvhen daily plasma estradiol (E 2) levels exceeded 3000 pmol/1 and when there were one or more follicles 1.4 em or larger in diameter, as measured by ultrasound.14 All of the patients were given 5000 IU of hCG (Pregnyl, Organon) to time the final phase of oocyte maturation and the time of laparoscopy (36 hours after hCG injection). hCG was administered when patients were within 3 days of the expected day of their LH surge, 13 after plasma E 2 levels had continuously increased for 6 days or more, and the largest follicles were 1. 7 em or larger in diameter. 14 During a 3-month period, 42 patients who consented to participate in the study were randomly allocated to one of three treatment groups. Group A patients were given the routine treatment for IVF, except for some additional blood sampling. Group B patients were given, in addition, an injection of 25 mg of P intramuscularly (Proluton, Schering, Berlin, West Germany) 21 to 24 hours Vol. 45, No. 4, April 1986
after hCG administration, 50 mg of P intramuscularly 35 hours after hCG administration (1 hour before laparoscopy), and 50 mg of P intramuscularly 24 hours after laparoscopy (60 hours after hCG administration). Group C patients were given a second injection of 5000 IU of hCG 24 hours after the initial injection of hCG used to time laparoscopy. Blood samples were taken from the patients at 8:00A.M., 2:00P.M., and 9:00P.M. the day before hCG injection and in the 36 hours before laparoscopy. Blood was taken 1 hour before laparoscopy and again 24 hours after laparoscopy. Plasma was separated immediately after recovery, stored frozen, and assayed for P concentration with a specific radioimmunoassay kit (Radioassay Systems Laboratories, Inc., Carson, CA). 12 Laparoscopy was performed for oocyte recovery at 9:00 A.M. to 11:00 A.M. (Figs. 1 and 2). Oocytes were recovered, inseminated, cultured in vitro, and transferred as previously described. 15-17
] ....... 20
E ..... Cl 5 15
A
8
C1)
c: 0
.....
C1)
10
iii C1) Cl
0 .....
5
a. a!
E
• Pregnant Not Pregnant
0
o
(/)
a!
ii:
15
c
10 5
coco co coco co co o
co o'O
Time (hr)
Figure 2 Mean P levels in patients who became pregnant and those who did not become pregnant after embryo replacement in each of the three treatment groups. Laparoscopy was carried out in all patients at 9:00A.M. to 11:00 A.M. on the third day shown. Trounson et al. Progesterone supplementation for IVF
533
Table 1. Fertilization and Embryo Development According to Treatment Treatment group No. of oocytes collected Oocytes fertilized No. % Embryos developed No. %
A
B
c
63
45
61
41 65
36 80
49 80
36 88
30 83
43 88
RESULTS
The. effect of P supplementation (group B) is shown in Figure 1. Peripheral plasma P levels were significantly higher in group B patients than in group A and C patients 35 hours (P < 0.001) and 60 hours (P < 0.001) after the initial hCG injection. This treatment removed the natural nadir of P secretion normally seen in superovulated patients at 8:00 A.M. and provided P supplementation during anesthesia and follicular aspiration (Fig. 1). There was a smaller, but not significant, increase in P secretion in group C at 35 and 60 hours after the initial hCG injection (Fig. 1). There was no difference in mean plasma P levels between patients who became pregnant and those who failed to become pregnant after embryo transfer (Fig. 2). Fertilization and embryo development rates were similar in all groups (Table 1). The mean number of embryos repll;J.ced in each group is shown in Table 2. The stage of development and morphologic quality of embryos replaced were the same in each group, and pregnancy rates were similar in each group (Table 2).
also unable to detect luteal phase defects in any· patient before day 7 after laparoscopy. 18 In addition, supplementation of the luteal phase from days 7 to 16 with intramuscular injection of 50 mg of P daily had no significant effect on improving pregnancy rate in a controlled trial reported by Leeton et al. 19 Given these observations, it is difficult to conclude that deficiencies of P secretion arising through superovulation and laparoscopy reduce uterine receptivity for embryo development or the initiation of pregnancy in human IVF. Our studies 10 have been concentrated on the combined schedule of CC and hMG for many years after our introduction of this superovulation protocol in 1981. Dlugi et al. 20 showed that the luteal phase in IVF cycles stimulated with CC alone is different from that in IVF cycles stimulated with hMG alone. On day 12 after laparoscopy, serum P levels are significantly lower in patients treated with hMG. The Norfolk IVF group has repeatedly drawn attention to the fact that P levels are higher in conception cycles than in nonconception cycles and that this difference is apparent within 24 hours of embryo transfer. 21 On this evidence, they recommend P support of the luteal phase in IVF. The difference of opinion in the need for P support therapy in IVF may be the result of differences between our own CC and hMG protocol and the hMG-alone superovulation protocol used by the Norfolk group. Alternatively, as demonstrated by Wood et al., 22 the higher P levels observed for the conception cycles in the Norfolk data may be because of the higher pregTable 2. Embryo Transfer and Pregnancy According to Treatment Treatment group
DISCUSSION
Our results indicate that supplementation of the P deficiency caused by anesthesia and follicular aspiration at the time of oocyte recovery 9 has no apparent effect on uterine receptivity for the initiation of pregnancy after embryo transfer. We previously reported 18 that plasma P levels at the time of embryo transfer were variable but higher than those observed for the spontaneous ovulatory cycle. Furthermore, P levels at the time of embryo replacement observed in conception cycles (39.5 ± 20.8; range, 8.6 t-e-&4.0 ng/ml) were no different from those of nonconceptional cycles (55.9 ± 43.1; range 8.5 to 145.0 ng/ml). We were 534
Trounson et al. Progesterone supplementation for IVF
Mean no. of embryos transferreda No. of patients with embryos transferred Patients pregnant No. %
No. of patients miscarried No. of ectopic pregnancies No. of patients delivered
A
B
c
2.0
2.1
2.6
14
14
14
4 29 1
4 29 1
4 29 1
0
0
1
3
3
2
aDue to the limitation of replacing a maximum of three embryos at embryo transfer, the remaining embryos were preserved by freezing.
Fertility and Sterility
nancy rate experienced in patients when larger numbers of follicles, oocytes, and embryos are obtained. These patients would logically have, on average, more corpora lutea and higher P levels during the early luteal phase. We conclude that in our own superovulation protocol, which involves a combination of CC and hMG, P supplementation around the time oflaparoscopy and during the luteal phase is unlikely to improve the success rate of human IVF.
REFERENCES 1. Mishell DR,. Thorneycroft IH, Nagata Y, Murata T, Nakam:ura R: Serum gonadotropin and steroid patterns in early human gestation. Am J Obstet Gynecol 117:631, 1973 2. Lenton EA, Sulaiman R, Sobowale 0 , Cooke ID: The human menstrual cycle: plasma concentrations of prolactin, LH, FSH, oestradiol and progesterone in conceiving and non-conceiving women. J Reprod Fertil 37:773, 1982 3. Kreitmann 0, Nixon WE, Hodgen GD: Induced corpus luteum dysfunction after aspiration of the preovulatory follicle in monkeys. Fertil Steril 35:671, 1981 4. Garcia J, Jones GS, Acosta AA, Wright GL Jr: Corpus luteum function after follicle aspiration for oocyte retrieval. Fertil Steril 36:565, 1981 5. Frydman R, Testart J, Giacomini P , Imbert MC, Martin E, Nahoul K: Hormonal and histological study of the luteal phase in women following aspiration of the preovulatory follicle. Fertil Steril 38:312, 1982 6. Kerin JFP, Warnes GM, Quinn T, Jeffrey R, Godfrey B, Hourigan L, Broom TJ, McEvoy M, Johnson M, Cox LW: The effect of Clomid-induced superovulation on human follicular and luteal function for extracorporeal fertilization and embryo transfer. J Clin Reprod Fertil· 2:129, 1984 7. Jones HW Jr: Factors influencing implantation and maintenance of pregnancy following embryo transfer. In Fertilization of the Human Egg In Vitro, Edited by HM Beier, HR Lindner. Berlin, Springer-Verlag, 1983, p 293 8. Jones GS: Update on in vitro fertilization. Endocr Rev 5:62, 1984 9. Taylor PJ, Trounson A, Besanko M, Burger HG, Stockdale J: Plasma progesterone and prolactin changes in superovulated women before, during and immediately after laparoscopy for in vitro fertilization and their relation to pregnancy. Fertil Steril. In press
Vol. 45, No. 4, April 1986
10. Trounson A, Conti A: Research in human in vitro fertilization and embryo transfer. Br Med J 285.:244, 1982 11. Trounson A: In vitro fertilization and embryo preservation. In In Vitro Fertilization and Embryo Transfer, Edited by A Trounson, C Wood. Edinburgh, Churchill Livingstone, 1984, p 111 12. Trounson AO, Calabrese R: Changes in plasma progesterone concentrations around the time of the luteinizing hormone surge in women superovulated for in vitro fertilization. J Clin Endocrinol Metab 59:1075, 1984 13. Mcintosh JEA, Matthews CD, Crocker JM, Broom TJ, Cox LW: Predicting the luteinizing hormone surge: relationship between the duration of the follicular and luteal phases and the length of the human menstrual cycle. Fertil Steril 34:125, 1980 14. Buttery B, Trounson A, McMaster R, Wood C: Evaluation of diagnostic ultrasound as a parameter of follicular development in an in vitro fertilization program. Fertil Steril 39:458, 1983 15. Trounson AO, Mohr LR, Wood C, Leeton JF: Effect of delayed insemination on in vitro fertilization, culture and transfer of human embryos. J Reprod Fertil64:285, 1982 16. Mahadevan MM, Trounson AO: The influence of seminal characteristics on the success rate of human in vitro fertilization. Fertil Steril 42:400, 1984 17. Leeton J, Trounson A, Jessup D, Wood C: The technique of human embryo transfer. Fertil Steril 38:156, 1982 18. Trounson A: Factors controlling normal embryo development and implantation of human oocytes fertilized in vitro. In Fertilization of the Human Egg In Vitro, Edited by HM Beier, HR Lindner. Berlin, Springer-Verlag, 1983, p 235 19. Leeton J , Trounson A, Jessup D: Support of the luteal phase in in vitro fertilization programmes: results of a controlled trial with intramuscular Proluton. J In Vitro Fertil Embryo Trans 2:166, 1985 20. Dlugi AM, Laufer N, Botero-Ruiz W, DeCherney AH, Polan ML, Haseltine FP, Mezer HC, Behrman HR: Altered follicular development in clomiphene citrate versus human menopausal gonadotropin-stimulated cycles for in vitro fertilization. Fertil Steril 43:40, 1985 21. Jones HW Jr, Acosta AA, Andrews MC, Garcia JE, Jones GS, Mayer J , McDowell JS, Rosenwaks Z, Sandow BA, Veeck LL, Wilkes CA: Three years of in vitro fertilization at Norfolk. Fertil Steril 42:826, 1984 22. Wood C, McMaster R, Rennie G, Trounson A, Leeton J : Factors influencing pregnancy rates following in vitro fertilization and embryo transfer. Fertil Steril 43:245, 1985
Trounson et al. Progesterone supplementation for IVF
535
Vol. 45, No. 4, April 1986 Printed in U.S -4. .
The effect of progesterone supplementation around the time of oocyte recovery in patients superovulated for in vitro fertilization
Alan Trounson, Ph.D.* Donna Howlett, B.Sc. Peter Rogers, Ph.D. Hans-Otto Hoppen, Ph.D. Centre for Early Human Development and Department of Obstetrics and Gynaecology, Monash University, Queen Victoria Medical Centre, Melbourne, Victoria, Australia
A randomized control trial involving 42 superovulated in vitro fertilization (IVF) patients was carried out to investigate the effects of providing supplementary progesterone (P) around the time of laparoscopy. P was given 12 to 15 hours and 1 hour before and 24 hours after laparoscopy in one group (group B); human chorionic gonadotropin was given 12 hours before laparoscopy in another group (group C); and the remainder received no treatment in addition to normal IVF procedures (group A). There was no difference in fertilization rate, the proportion of normally developing embryos, pregnancy rate, or birth rate between the treatment groups. We conclude that in the superovulation schedule used, P supplementation around the time qf laparoscopy does not affect success rate of IVF. Fertil Steril45:532, 1986
The hormonal profiles of conception cycles are characterized by sustained luteal progesterone (P) secretion, although the range of peripheral concentrations of P compatible with pregnancy is not well defined, despite several well-planned studies. 1 • 2 In the study reported by Lenton et al., 2 P concentrations were higher in the conception group, particularly 3 to 8 days after the luteinizing hormone (LH) surge. Reduced P secretion and luteal dysfunction have been noted in monkeys 3 and humans 4 · 5 after follicular aspiration for oocyte recovery in the natural ovulatory cycle. In women superovulated for in vitro fertilization (IVF), plasma P levels are considerably higher than in the natural ovulatory cycle, because of multiple corpora lutea. Reduced P secretion and Received September 10, 1985; revised and accepted December 26, 1985. *Reprint requests: Dr. Alan Trounson, Centre for Early Human Development, Queen Victoria Medical Centre, 172 Lonsdale Street, Melbourne, Victoria, Australia 3000. 532
Trounson et al. Progesterone supplementation for IVF
luteal defects are not readily apparent under these circumstances. 5 • 6 However, there are some reports 7 • 8 that patients superovulated with human menopausal gonadotropin (hMG), with higher luteal phase P levels, particularly days 3 to 8 after laparoscopy, are more likely to become pregnant after embryo transfer. In our studies, we have observed a major reduction in peripheral plasma P during anesthesia and follicular aspiration for oocyte recovery, particularly in some individual patients. 9 These experiments were undertaken to investigate whether supplementation of P levels around the time of laparoscopy by the administration of exogenous P or human chorionic gonadotropin (hCG) would improve the chance of pregnancy for IVF patients. MATERIALS AND METHODS
The study was carried out with patients attending the Monash-Epworth IVF program. SuperFertility and Sterility
25 .......
E ..... Cl 20
c: ........
8
C1)
c: 0 .....
-
15
C1)
( /)
C1)
Cl 0
.....
10
a.
a!
E (/)
a!
5
ii:
0
Time (hr)
Figure 1 P levels ( ± standard error of the mean) in IVF patients around the time of laparoscopy following normal procedures (A), supplementation with exogenous P (B ), or a supplementary injection of hCG (C).
ovulation was induced with a combination of clomiphene citrate (CC; Clomid, Merrell and Company, Sydney, NSW, Australia) and hMG (Humegon, Organon, Sydney, NSW, Australia), as previously described.10-12 CC was given at a dose of 50 to 150 mg daily for 5 days, beginning 10 days before the expected mean day of the LH surge. 13 On the second day of CC administration, the patients were given 75 to 225 IU of hMG for 2 to 5 days. The hMG treatment was stopped yvhen daily plasma estradiol (E 2) levels exceeded 3000 pmol/1 and when there were one or more follicles 1.4 em or larger in diameter, as measured by ultrasound.14 All of the patients were given 5000 IU of hCG (Pregnyl, Organon) to time the final phase of oocyte maturation and the time of laparoscopy (36 hours after hCG injection). hCG was administered when patients were within 3 days of the expected day of their LH surge, 13 after plasma E 2 levels had continuously increased for 6 days or more, and the largest follicles were 1. 7 em or larger in diameter. 14 During a 3-month period, 42 patients who consented to participate in the study were randomly allocated to one of three treatment groups. Group A patients were given the routine treatment for IVF, except for some additional blood sampling. Group B patients were given, in addition, an injection of 25 mg of P intramuscularly (Proluton, Schering, Berlin, West Germany) 21 to 24 hours Vol. 45, No. 4, April 1986
after hCG administration, 50 mg of P intramuscularly 35 hours after hCG administration (1 hour before laparoscopy), and 50 mg of P intramuscularly 24 hours after laparoscopy (60 hours after hCG administration). Group C patients were given a second injection of 5000 IU of hCG 24 hours after the initial injection of hCG used to time laparoscopy. Blood samples were taken from the patients at 8:00A.M., 2:00P.M., and 9:00P.M. the day before hCG injection and in the 36 hours before laparoscopy. Blood was taken 1 hour before laparoscopy and again 24 hours after laparoscopy. Plasma was separated immediately after recovery, stored frozen, and assayed for P concentration with a specific radioimmunoassay kit (Radioassay Systems Laboratories, Inc., Carson, CA). 12 Laparoscopy was performed for oocyte recovery at 9:00 A.M. to 11:00 A.M. (Figs. 1 and 2). Oocytes were recovered, inseminated, cultured in vitro, and transferred as previously described. 15-17
] ....... 20
E ..... Cl 5 15
A
8
C1)
c: 0
.....
C1)
10
iii C1) Cl
0 .....
5
a. a!
E
• Pregnant Not Pregnant
0
o
(/)
a!
ii:
15
c
10 5
coco co coco co co o
co o'O
Time (hr)
Figure 2 Mean P levels in patients who became pregnant and those who did not become pregnant after embryo replacement in each of the three treatment groups. Laparoscopy was carried out in all patients at 9:00A.M. to 11:00 A.M. on the third day shown. Trounson et al. Progesterone supplementation for IVF
533
Table 1. Fertilization and Embryo Development According to Treatment Treatment group No. of oocytes collected Oocytes fertilized No. % Embryos developed No. %
A
B
c
63
45
61
41 65
36 80
49 80
36 88
30 83
43 88
RESULTS
The. effect of P supplementation (group B) is shown in Figure 1. Peripheral plasma P levels were significantly higher in group B patients than in group A and C patients 35 hours (P < 0.001) and 60 hours (P < 0.001) after the initial hCG injection. This treatment removed the natural nadir of P secretion normally seen in superovulated patients at 8:00 A.M. and provided P supplementation during anesthesia and follicular aspiration (Fig. 1). There was a smaller, but not significant, increase in P secretion in group C at 35 and 60 hours after the initial hCG injection (Fig. 1). There was no difference in mean plasma P levels between patients who became pregnant and those who failed to become pregnant after embryo transfer (Fig. 2). Fertilization and embryo development rates were similar in all groups (Table 1). The mean number of embryos repll;J.ced in each group is shown in Table 2. The stage of development and morphologic quality of embryos replaced were the same in each group, and pregnancy rates were similar in each group (Table 2).
also unable to detect luteal phase defects in any· patient before day 7 after laparoscopy. 18 In addition, supplementation of the luteal phase from days 7 to 16 with intramuscular injection of 50 mg of P daily had no significant effect on improving pregnancy rate in a controlled trial reported by Leeton et al. 19 Given these observations, it is difficult to conclude that deficiencies of P secretion arising through superovulation and laparoscopy reduce uterine receptivity for embryo development or the initiation of pregnancy in human IVF. Our studies 10 have been concentrated on the combined schedule of CC and hMG for many years after our introduction of this superovulation protocol in 1981. Dlugi et al. 20 showed that the luteal phase in IVF cycles stimulated with CC alone is different from that in IVF cycles stimulated with hMG alone. On day 12 after laparoscopy, serum P levels are significantly lower in patients treated with hMG. The Norfolk IVF group has repeatedly drawn attention to the fact that P levels are higher in conception cycles than in nonconception cycles and that this difference is apparent within 24 hours of embryo transfer. 21 On this evidence, they recommend P support of the luteal phase in IVF. The difference of opinion in the need for P support therapy in IVF may be the result of differences between our own CC and hMG protocol and the hMG-alone superovulation protocol used by the Norfolk group. Alternatively, as demonstrated by Wood et al., 22 the higher P levels observed for the conception cycles in the Norfolk data may be because of the higher pregTable 2. Embryo Transfer and Pregnancy According to Treatment Treatment group
DISCUSSION
Our results indicate that supplementation of the P deficiency caused by anesthesia and follicular aspiration at the time of oocyte recovery 9 has no apparent effect on uterine receptivity for the initiation of pregnancy after embryo transfer. We previously reported 18 that plasma P levels at the time of embryo transfer were variable but higher than those observed for the spontaneous ovulatory cycle. Furthermore, P levels at the time of embryo replacement observed in conception cycles (39.5 ± 20.8; range, 8.6 t-e-&4.0 ng/ml) were no different from those of nonconceptional cycles (55.9 ± 43.1; range 8.5 to 145.0 ng/ml). We were 534
Trounson et al. Progesterone supplementation for IVF
Mean no. of embryos transferreda No. of patients with embryos transferred Patients pregnant No. %
No. of patients miscarried No. of ectopic pregnancies No. of patients delivered
A
B
c
2.0
2.1
2.6
14
14
14
4 29 1
4 29 1
4 29 1
0
0
1
3
3
2
aDue to the limitation of replacing a maximum of three embryos at embryo transfer, the remaining embryos were preserved by freezing.
Fertility and Sterility
nancy rate experienced in patients when larger numbers of follicles, oocytes, and embryos are obtained. These patients would logically have, on average, more corpora lutea and higher P levels during the early luteal phase. We conclude that in our own superovulation protocol, which involves a combination of CC and hMG, P supplementation around the time oflaparoscopy and during the luteal phase is unlikely to improve the success rate of human IVF.
REFERENCES 1. Mishell DR,. Thorneycroft IH, Nagata Y, Murata T, Nakam:ura R: Serum gonadotropin and steroid patterns in early human gestation. Am J Obstet Gynecol 117:631, 1973 2. Lenton EA, Sulaiman R, Sobowale 0 , Cooke ID: The human menstrual cycle: plasma concentrations of prolactin, LH, FSH, oestradiol and progesterone in conceiving and non-conceiving women. J Reprod Fertil 37:773, 1982 3. Kreitmann 0, Nixon WE, Hodgen GD: Induced corpus luteum dysfunction after aspiration of the preovulatory follicle in monkeys. Fertil Steril 35:671, 1981 4. Garcia J, Jones GS, Acosta AA, Wright GL Jr: Corpus luteum function after follicle aspiration for oocyte retrieval. Fertil Steril 36:565, 1981 5. Frydman R, Testart J, Giacomini P , Imbert MC, Martin E, Nahoul K: Hormonal and histological study of the luteal phase in women following aspiration of the preovulatory follicle. Fertil Steril 38:312, 1982 6. Kerin JFP, Warnes GM, Quinn T, Jeffrey R, Godfrey B, Hourigan L, Broom TJ, McEvoy M, Johnson M, Cox LW: The effect of Clomid-induced superovulation on human follicular and luteal function for extracorporeal fertilization and embryo transfer. J Clin Reprod Fertil· 2:129, 1984 7. Jones HW Jr: Factors influencing implantation and maintenance of pregnancy following embryo transfer. In Fertilization of the Human Egg In Vitro, Edited by HM Beier, HR Lindner. Berlin, Springer-Verlag, 1983, p 293 8. Jones GS: Update on in vitro fertilization. Endocr Rev 5:62, 1984 9. Taylor PJ, Trounson A, Besanko M, Burger HG, Stockdale J: Plasma progesterone and prolactin changes in superovulated women before, during and immediately after laparoscopy for in vitro fertilization and their relation to pregnancy. Fertil Steril. In press
Vol. 45, No. 4, April 1986
10. Trounson A, Conti A: Research in human in vitro fertilization and embryo transfer. Br Med J 285.:244, 1982 11. Trounson A: In vitro fertilization and embryo preservation. In In Vitro Fertilization and Embryo Transfer, Edited by A Trounson, C Wood. Edinburgh, Churchill Livingstone, 1984, p 111 12. Trounson AO, Calabrese R: Changes in plasma progesterone concentrations around the time of the luteinizing hormone surge in women superovulated for in vitro fertilization. J Clin Endocrinol Metab 59:1075, 1984 13. Mcintosh JEA, Matthews CD, Crocker JM, Broom TJ, Cox LW: Predicting the luteinizing hormone surge: relationship between the duration of the follicular and luteal phases and the length of the human menstrual cycle. Fertil Steril 34:125, 1980 14. Buttery B, Trounson A, McMaster R, Wood C: Evaluation of diagnostic ultrasound as a parameter of follicular development in an in vitro fertilization program. Fertil Steril 39:458, 1983 15. Trounson AO, Mohr LR, Wood C, Leeton JF: Effect of delayed insemination on in vitro fertilization, culture and transfer of human embryos. J Reprod Fertil64:285, 1982 16. Mahadevan MM, Trounson AO: The influence of seminal characteristics on the success rate of human in vitro fertilization. Fertil Steril 42:400, 1984 17. Leeton J, Trounson A, Jessup D, Wood C: The technique of human embryo transfer. Fertil Steril 38:156, 1982 18. Trounson A: Factors controlling normal embryo development and implantation of human oocytes fertilized in vitro. In Fertilization of the Human Egg In Vitro, Edited by HM Beier, HR Lindner. Berlin, Springer-Verlag, 1983, p 235 19. Leeton J , Trounson A, Jessup D: Support of the luteal phase in in vitro fertilization programmes: results of a controlled trial with intramuscular Proluton. J In Vitro Fertil Embryo Trans 2:166, 1985 20. Dlugi AM, Laufer N, Botero-Ruiz W, DeCherney AH, Polan ML, Haseltine FP, Mezer HC, Behrman HR: Altered follicular development in clomiphene citrate versus human menopausal gonadotropin-stimulated cycles for in vitro fertilization. Fertil Steril 43:40, 1985 21. Jones HW Jr, Acosta AA, Andrews MC, Garcia JE, Jones GS, Mayer J , McDowell JS, Rosenwaks Z, Sandow BA, Veeck LL, Wilkes CA: Three years of in vitro fertilization at Norfolk. Fertil Steril 42:826, 1984 22. Wood C, McMaster R, Rennie G, Trounson A, Leeton J : Factors influencing pregnancy rates following in vitro fertilization and embryo transfer. Fertil Steril 43:245, 1985
Trounson et al. Progesterone supplementation for IVF
535