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Endogenous luteinizing hormone surge and superovulation
FERTILITY AND STERILITY Copyright 0 1988 The American Fertility Society
Vol. 49, No.1, January 1988 Printed in U.S.A.
Endogenous luteinizing hormone surge and superovulation
Luther M. Talbert, M.D. Professor Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of North Carolina, Chapel Hill, North Carolina
Received November 6, 1987. Reprint requests: Luther M. Talbert, M.D., Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, CB# 7570, MacNider Building, University of North Carolina, Chapel Hill, North Carolina 27599.
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Talbert Editor's corner
Ferraretti and colleagues 1 observed in 1983 that normally cycling women being treated with human menopausal gonadotropin (hMG) according to the Norfolk protocol failed to mount the expected endogenous luteinizing hormone (LH) surge. Subsequent investigators have shown that the LH surge is not completely suppressed during treatment with exogenous gonadotropins, but that higher levels of serum estrogen are required to trigger the surge and that most patients do not surge even with serum estradiol (E 2 ) levels of 500 pglml or greater. 2- 5 It has been suggested that hyperstimulated ovarian follicles may secrete sufficient ovarian inhibin to reduce effectively the ability of the pituitary to respond to the positive feedback effect of estrogen. 1 Indeed, Schenken and Hodgen6 showed, in normally cycling cynomolgus monkeys, that hyperstimulation with hMG is associated with a greatly reduced incidence of LH surges and that the pituitary response to bolus injection of gonadotropin-releasing hormone (GnRH) is reduced markedly in animals so treated. That the substance (S) responsible for this effect is short-lived and of ovarian origin was shown by the return of normal pituitary responsiveness within 30 minutes after bilateral oophorectomy.6 The probability that an LH surge will occur incident to ovarian hyperstimulation is determined, to an extent, by the stimulation protocol, and a lower incidence of surges has been reported in patients receiving a combination of clomiphene citrate (CC) and hMG. Thus, Vargyas et al. 7 reported that 33% of patients receiving hMG alone showed surge, whereas 0% to 15% of patients receiving a combination protocol of CC plus hMG showed surge, depending on the specific drug sequence. Although pregnancy rates based on the number of laparoscopies was higher in the hMG only group, the difference did not reach statistical significance. 7 Data from the University of North Carolina programS is consistent with that presented by Vargyas and colleagues. 7 From January 1, 1986, through April 30, 1987, 239 patients began stimulation for in vitro fertilization (IVF) in our program. One hundred fifty-seven patients were treated with hMG alone and 33 (21%) had an LH surge. Among 82 patients stimulated with a CCI hMG protocol, only 8 (9.8%) demonstrated surge, despite higher serum E2 levels in the latter group. In the University of North Carolina Program, a surge is defined as doubling of the baseline value obtained on day 5 of stimulation and an absolute value of ~30 mIU I ml. Cycles in which a surge occurs are discontinued. When an LH surge occurs, most IVF programs recommend that the cycle be terminated. This recommendation is based on the observed lower pregnancy rates in such cycles. Lejeune et al. 3 reported no clinical pregnancies in 21 cycles with an LH surge, and 16 pregnancies out Fertility and Sterility
of 100 cycles when an LH surge did not occur. Eibschitz and colleagues2 found reduced pregnancy rates when an LH surge occurred. When the surge occurred with a serum E2 of :s;1200 pg/ml and there were fewer than three follicles ~ 14 ml, the oocyte recovery rate per follicle was 31 %. When the surge occurred with the serum E2 ~ 1200 pg/ml and three or more follicles were ~14 ml, recovery rate per follicle was 80%. When oocytes were obtained after an LH surge, however, the embryo cleavage rate and pregnancy rates per transfer were similar to those of patients without a surge. 2 These authors recommended that cycles be interrupted when a surge occurred in the absence of optimal criteria. Conversely, Huang et al. noted that patients with an LH surge had pregnancy rates identical to those of nonsurge patients. Surge patients who had a serum E2 of >300 pglfollicle ~ 16 ml were given human chorionic gonadotropin (hCG) the afternoon of the same day and oocyte collection was done the next morning at 8 or 9 A.M.5 This issue contains two articles relevant to the subject. Glasier et a1. 9 define an LH surge as an 80% increase of serum LH relative to the mean of the previous 4 days, a continued rise of serum LH, and a rise in serum progesterone that is sustained. Based on these criteria, there was a high incidence of LH surges in hMG-treated women. Since most programs now cancel cycles in which an LH surge occurs, two approaches to the problem seem reasonable. If the surge could be predicted, hCG could be administered coincidentally and the cycle might be salvaged. The article by Serafini and colleagueslO suggests that a rise in serum progesterone (P) in the morning indicates an impending LH surge and might allow salvage of otherwise abandoned cycles. The alternative approach is prevention of the LH surge entirely. Further experience with the GnRH agonists and antagonists may make it feasible to eliminate surges by appropriate pretreatment and thus salvage a significant number of otherwise lost cycles. The articles in this issue may hasten progress toward that goal. Finally, when serum or urine LH can be measured at frequent intervals, scheduling of oocyte aspiration can be based on the time of onset of the
Vol. 49, No.1, January 1988
surge and pregnancy rates do not appear to be adversely affected. Thus, Macnamee and Howles l l reported 238 patients with LH surges detected by measurement of urine LH every 4 hours. The pregnancy rate in the patients did not differ from that of 925 control patients without a surge. Because most programs do not have facilities or personnel for 4 hourly LH determinations, it is likely that further development of GnRH agonists and antagonists will occur and allow a greater number of patients to complete initiated IVF attempts. REFERENCES 1. Ferraretti AP, Garcia JE, Acosta A, Jones GS: Serum luteinizing hormone during ovulation induction with human menopausal gonadotropin for in vitro fertilization in normally menstruating women. Fertil Steril 40:742, 1983 2. Eibschitz I, Belaisch-Allart JC, Frydman R: In vitro fertilization management and results in stimulated cycles with spontaneous luteinizing hormone discharge. Fertil Steril 45:231, 1986 3. Lejeune B, Degueldre M, Camus M, Vekemans M, Opsomer L, Leroy F: In vitro fertilization and embryo transfer as related to endogenous luteinizing hormone rise or human chorionic gonadotropin administration. Fertil SteriI45:377, 1986 4. Nader S, Berkowitz AS, Maklad N, Wolf DP, Held B: Characteristics of patients with and without gonadotropin surges during follicular recruitment in an in vitro fertilization/embryo transfer program. Fertil Steril 45:75, 1986 5. Huang K-E, Chang SY, Muechler EK, Graham MC: The outcome of continued treatment of luteinizing hormonesurged cycles in in vitro fertilization with the use of human menopausal gonadotropin. Fertil SteriI47:816, 1987 6. Schenken RS, Hodgen GD: Follicle-stimulating hormone induced ovarian hyperstimulation in monkeys: blockage of the luteinizing hormone surge. J Clin Invest 57:50, 1983 7. Vargyas JM, Morente C, Shangold G, Marrs RP: The effect of different methods of ovarian stimulation for human in vitro fertilization and embryo replacement. Fertil Steril 42:745, 1984 8. Talbert LM, Hammond MG: Unpublished data 9. Glasier A, Thatcher SS, Wickings EJ, Hillier SG, Baird DT: Superovulation with exogenous gonadotropins does not inhibit the luteinizing hormone surge. Fertil Steril 49:81, 1988 10. Serafini P, Stone B, Kerin J, Batzofin J, Quinn P, Marrs R: Occurrence of a spontaneous luteinizing hormone surge in superovulated cycles-predictive value of serum progesterone. Fertil Steril 49:86, 1988 11. Macnamee MC, Howles CM: The occurrence, characteristics and management of the LH surge in IVF. Hum Reprod 2(suppl 1):46, 1987
Talbert Editor's corner
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Vol. 49, No.1, January 1988 Printed in U.S.A.
Endogenous luteinizing hormone surge and superovulation
Luther M. Talbert, M.D. Professor Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of North Carolina, Chapel Hill, North Carolina
Received November 6, 1987. Reprint requests: Luther M. Talbert, M.D., Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, CB# 7570, MacNider Building, University of North Carolina, Chapel Hill, North Carolina 27599.
24
Talbert Editor's corner
Ferraretti and colleagues 1 observed in 1983 that normally cycling women being treated with human menopausal gonadotropin (hMG) according to the Norfolk protocol failed to mount the expected endogenous luteinizing hormone (LH) surge. Subsequent investigators have shown that the LH surge is not completely suppressed during treatment with exogenous gonadotropins, but that higher levels of serum estrogen are required to trigger the surge and that most patients do not surge even with serum estradiol (E 2 ) levels of 500 pglml or greater. 2- 5 It has been suggested that hyperstimulated ovarian follicles may secrete sufficient ovarian inhibin to reduce effectively the ability of the pituitary to respond to the positive feedback effect of estrogen. 1 Indeed, Schenken and Hodgen6 showed, in normally cycling cynomolgus monkeys, that hyperstimulation with hMG is associated with a greatly reduced incidence of LH surges and that the pituitary response to bolus injection of gonadotropin-releasing hormone (GnRH) is reduced markedly in animals so treated. That the substance (S) responsible for this effect is short-lived and of ovarian origin was shown by the return of normal pituitary responsiveness within 30 minutes after bilateral oophorectomy.6 The probability that an LH surge will occur incident to ovarian hyperstimulation is determined, to an extent, by the stimulation protocol, and a lower incidence of surges has been reported in patients receiving a combination of clomiphene citrate (CC) and hMG. Thus, Vargyas et al. 7 reported that 33% of patients receiving hMG alone showed surge, whereas 0% to 15% of patients receiving a combination protocol of CC plus hMG showed surge, depending on the specific drug sequence. Although pregnancy rates based on the number of laparoscopies was higher in the hMG only group, the difference did not reach statistical significance. 7 Data from the University of North Carolina programS is consistent with that presented by Vargyas and colleagues. 7 From January 1, 1986, through April 30, 1987, 239 patients began stimulation for in vitro fertilization (IVF) in our program. One hundred fifty-seven patients were treated with hMG alone and 33 (21%) had an LH surge. Among 82 patients stimulated with a CCI hMG protocol, only 8 (9.8%) demonstrated surge, despite higher serum E2 levels in the latter group. In the University of North Carolina Program, a surge is defined as doubling of the baseline value obtained on day 5 of stimulation and an absolute value of ~30 mIU I ml. Cycles in which a surge occurs are discontinued. When an LH surge occurs, most IVF programs recommend that the cycle be terminated. This recommendation is based on the observed lower pregnancy rates in such cycles. Lejeune et al. 3 reported no clinical pregnancies in 21 cycles with an LH surge, and 16 pregnancies out Fertility and Sterility
of 100 cycles when an LH surge did not occur. Eibschitz and colleagues2 found reduced pregnancy rates when an LH surge occurred. When the surge occurred with a serum E2 of :s;1200 pg/ml and there were fewer than three follicles ~ 14 ml, the oocyte recovery rate per follicle was 31 %. When the surge occurred with the serum E2 ~ 1200 pg/ml and three or more follicles were ~14 ml, recovery rate per follicle was 80%. When oocytes were obtained after an LH surge, however, the embryo cleavage rate and pregnancy rates per transfer were similar to those of patients without a surge. 2 These authors recommended that cycles be interrupted when a surge occurred in the absence of optimal criteria. Conversely, Huang et al. noted that patients with an LH surge had pregnancy rates identical to those of nonsurge patients. Surge patients who had a serum E2 of >300 pglfollicle ~ 16 ml were given human chorionic gonadotropin (hCG) the afternoon of the same day and oocyte collection was done the next morning at 8 or 9 A.M.5 This issue contains two articles relevant to the subject. Glasier et a1. 9 define an LH surge as an 80% increase of serum LH relative to the mean of the previous 4 days, a continued rise of serum LH, and a rise in serum progesterone that is sustained. Based on these criteria, there was a high incidence of LH surges in hMG-treated women. Since most programs now cancel cycles in which an LH surge occurs, two approaches to the problem seem reasonable. If the surge could be predicted, hCG could be administered coincidentally and the cycle might be salvaged. The article by Serafini and colleagueslO suggests that a rise in serum progesterone (P) in the morning indicates an impending LH surge and might allow salvage of otherwise abandoned cycles. The alternative approach is prevention of the LH surge entirely. Further experience with the GnRH agonists and antagonists may make it feasible to eliminate surges by appropriate pretreatment and thus salvage a significant number of otherwise lost cycles. The articles in this issue may hasten progress toward that goal. Finally, when serum or urine LH can be measured at frequent intervals, scheduling of oocyte aspiration can be based on the time of onset of the
Vol. 49, No.1, January 1988
surge and pregnancy rates do not appear to be adversely affected. Thus, Macnamee and Howles l l reported 238 patients with LH surges detected by measurement of urine LH every 4 hours. The pregnancy rate in the patients did not differ from that of 925 control patients without a surge. Because most programs do not have facilities or personnel for 4 hourly LH determinations, it is likely that further development of GnRH agonists and antagonists will occur and allow a greater number of patients to complete initiated IVF attempts. REFERENCES 1. Ferraretti AP, Garcia JE, Acosta A, Jones GS: Serum luteinizing hormone during ovulation induction with human menopausal gonadotropin for in vitro fertilization in normally menstruating women. Fertil Steril 40:742, 1983 2. Eibschitz I, Belaisch-Allart JC, Frydman R: In vitro fertilization management and results in stimulated cycles with spontaneous luteinizing hormone discharge. Fertil Steril 45:231, 1986 3. Lejeune B, Degueldre M, Camus M, Vekemans M, Opsomer L, Leroy F: In vitro fertilization and embryo transfer as related to endogenous luteinizing hormone rise or human chorionic gonadotropin administration. Fertil SteriI45:377, 1986 4. Nader S, Berkowitz AS, Maklad N, Wolf DP, Held B: Characteristics of patients with and without gonadotropin surges during follicular recruitment in an in vitro fertilization/embryo transfer program. Fertil Steril 45:75, 1986 5. Huang K-E, Chang SY, Muechler EK, Graham MC: The outcome of continued treatment of luteinizing hormonesurged cycles in in vitro fertilization with the use of human menopausal gonadotropin. Fertil SteriI47:816, 1987 6. Schenken RS, Hodgen GD: Follicle-stimulating hormone induced ovarian hyperstimulation in monkeys: blockage of the luteinizing hormone surge. J Clin Invest 57:50, 1983 7. Vargyas JM, Morente C, Shangold G, Marrs RP: The effect of different methods of ovarian stimulation for human in vitro fertilization and embryo replacement. Fertil Steril 42:745, 1984 8. Talbert LM, Hammond MG: Unpublished data 9. Glasier A, Thatcher SS, Wickings EJ, Hillier SG, Baird DT: Superovulation with exogenous gonadotropins does not inhibit the luteinizing hormone surge. Fertil Steril 49:81, 1988 10. Serafini P, Stone B, Kerin J, Batzofin J, Quinn P, Marrs R: Occurrence of a spontaneous luteinizing hormone surge in superovulated cycles-predictive value of serum progesterone. Fertil Steril 49:86, 1988 11. Macnamee MC, Howles CM: The occurrence, characteristics and management of the LH surge in IVF. Hum Reprod 2(suppl 1):46, 1987
Talbert Editor's corner
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