Gynecology-endocrinology Vol. 57, No.2, February 1992
FERTILITY AND STERILITY
Printed on acid-free paper in U.S.A.
Copyright to 1992 The American Fertility Society
The response of patients with polycystic ovarian disease to human menopausal gonadotropin therapy after ovarian electrocautery or a luteinizing hormone-releasing hormone agonist*
Ahmed Abdel Gadir, Ph.D.t:\: Huda M. I. Alnaser, M.B.Ch.B.§ Rawof S. Mowafi, M.D.§ Robert W. Shaw, M.D.II Faculty of Medicine and Maternity Hospital, Safat, Kuwait, and the Royal Free Hospital, London, United Kingdom
Objective: To compare the effect of ovarian electrocautery versus an intranasal (IN) luteinizing hormone-releasing hormone agonist (LH-RH-a) in the response of patients with polycystic ovarian disease (PCOD) to human menopausal gonadotropin (hMG) therapy. Design: A prospective study with serial randomization of patients in two groups for treatment with ovarian electrocautery + hMG or LH-RH-a + hMG. Setting: A teaching hospital reproductive endocrinology clinic. Patients: Thirty-three women with PCOD who failed to conceive after six treatment cycles with hMG. Main Outcome Measures: Midcycle and luteal phase endocrinology, ovulation, pregnancy rates (PRs), and miscarriage rates. Results: There was no difference in the ovulation or PRs between the two groups. However, the number of cycles with multiple dominant follicles, the luteal phase serum testosterone, and the miscarriage rate were lower in the group pretreated with ovarian electrocautery. Conclusions: Pretreatment of patients with PCOD with ovarian electrocautery may be a better alternative to IN LH-RH-a therapy for induction of ovulation with hMG. Fertil Steril1992;57:309-13 Key Words: Ovarian electrocautery, pituitary desensitization, induction of ovulation, polycystic ovarian disease
Laparoscopic ovarian electrocautery and luteinizing hormone-releasing hormone agonists (LH-RH-a) are alternative modalities used for induction of ovu-
Received August 12, 1991; revised and accepted October 23, 1991. * Supported by grants MO 024 and RMU 149 from the Central Research Unit, Kuwait University, Kuwait. t Academic Department of Obstetrics and Gynaecology, Faculty of Medicine, Kuwait University Health Science Center, Kuwait. :j: Reprint requests: A. Abdel Gadir, Ph.D., Academic Department of Obstetrics and Gynaecology, Royal Free Hospital, Pond Street, London NW3 2QG, United Kingdom. § Maternity Hospital. II Academic Department of Obstetrics and Gynaecology, The Royal Free Hospital. Vol. 57, No.2, February 1992
lation in patients with polycystic ovarian disease (peOD) not responsive to simpler medications (15). We have already shown that ovarian electrocautery caused reduction in the level of serum testosterone (T) and luteinizing hormone (LH) values equivalent to the changes that follQwed 8 weeks of intranasal (IN) buserelin acetate medication (Suprefact; Hoechst Pharmaceuticals, Frankfurt, Germany) in a dose of 800 ~g/d. However, there was a further advantage of increased follicle-stimulating hormone level (FSH) after ovarian electrocautery (6). We also showed that successful induction of ovulation, pregnancy rates (PRs), and abortion rates after ovarian electrocautery were equivalent to the corresponding rates that followed treatment with Abdel Gadir et al.
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309
human menopausal gonadotropin (hMG) and pure FSH (7). At the same time, there was improvement in the clinical response to clomiphene citrate (CC) therapy after ovarian electrocautery in patients who were initially nonresponsive. This may reflect the reduction in LH and T values and the increase in FSH level documented during hormone pulse analysis even in patients who did not ovulate after the procedure (8). On the other hand, combining LHRH-a with hMG therapy was shown to improve the PR in patients with PCOD as compared with hMG only (9). However, LH-RH-a therapy was not shown to reduce multiple follicular recruitment or the hyperstimulation rate. In this report, we compared the effect of laparoscopic ovarian electrocautery versus IN buserelin acetate medication on the response of patients with PCOD to hMG medication. MATERIALS AND METHODS Patients
Thirty-three women with PCOD consented to participate in the study. They had failed previously to conceive after six treatment cycles with hMG therapy. All patients were oligomenorrhoeic or amenorrhoeic with clinical or biochemical hyperandrogenization (T ~ 3 nmoljL), serum LH exceeding 10 lUlL, or a high LH:FSH ratio (>2:1), and in all cases ultrasonically visualized polycystic ovaries (10). All patients had normal prolactin (PRL), dehydroepiandrosterone sulfate, and 17ahydroxyprogesterone values. There was no other contributing factor to their infertility as verified by repeated investigations. All medications known to affect the hormonal milieu were suspended for 3 months before this study. Patients were divided at random into two groups with serial alternating entry after random allocation of the first case (11). Sixteen women were treated with ovarian electrocautery followed by hMG (group A) and 17 were treated with IN buserelin acetate and hMG (group B). Patients' age, body mass index (BMI in kg/m 2 ), and ovarian volume (12) were documented. An Aloka Echo Camera LS-Model SSD-248 ultrasonic machine with 3.5-MHz sector probe (Aloka Corporation, Tokyo, Japan) was used for monitoring ovulation using the full bladder technique. All women were examined laparoscopically with chromohydrotubation, and group A patients had ovarian electrocautery as described previously (6). This was followed by hMG therapy (Pergonal; Serono Laboratories, Rome, Italy) starting on the 3rd day after surgery. Treat310
Abdel Gadir et al.
Electrocautery versus desensitization
ment was started with one ampule (75 IU FSH and 75 IU LH), and the dose was decided individually for each patient as described previously (7). Blood samples were taken on the same day, 3rd, 7th, and 9th day after surgery, and as necessary thereafter and assessed for estradiol (E 2), FSH, LH, total T, and PRL. In the following cycles, the last effective dose used in the previous cycle was given as the starting dose on the 2nd day of menstruation. Blood samples were collected on the same day, 4th, 7th, and 9th days after starting hMG, and as necessary thereafter and assessed for the same hormones. The LH surge was diagnosed by examination of urine samples using Ovustick (Monoclonal Antibodies, Inc, Wheatley, Oxford, United Kingdom) done serially starting at follicular diameter of 14 mm or 2 days after the beginning of the cervical mucus biological shift (13) as reported by the patient and verified by the examiners. Human chorionic gonadotropin (hCG) (5,000 IU) was given at follicular diameter of 18 mm and serum E2 of 1,000 pmoljL per mature follicle (:::::15 mm). The hCG dose was not given if more than three mature follicles were seen and in cycles with a spontaneous LH surge. Blood samples were collected on the 3rd, 6th, and 9th days after hCG and assessed for serum progesterone (P), PRL, and T. Ultrasonic scan examinations were done on the same days to diagnose ovulation. Patients in group B were started on buserelin acetate IN medication immediately after diagnostic laparoscopy in a dose of 800 Jlg/d for 8 weeks. They were followed with weekly estimations of FSH, LH, E 2, and T to monitor response. Eight weeks later, they were started on hMG medication for induction of ovulation in the same pattern as for the first group. In addition, 2,000 IU of hCG were given every 3 days after the initial 5,000 IU dose to supplement the corpus luteum (CL) for a total of three doses. Buserelin acetate medication was continued throughout the whole study period. Treatment was offered for six cycles in both groups unless pregnancy occurred. All hormones were assayed in duplicates using radioimmunoassay as described previously (6, 7). Statistical analysis of the data was done using MannWhitney, X2 (after Yate's correction), and Fisher's exact tests when applicable. The Statistical Package for Social Studies Computer Programme (SPSSI PC+) was used for data analysis. Values are given as the mean with 95% confidence interval (CI). RESULTS
There were no differences in the pretreatment biophysical or endocrine criteria between the two Fertility and Sterility
Table 1
Biophysical and Hormonal Criteria of Patients Before Any Medication· Group B (n = 17)
Group A (n = 16) Age (y) BMI (kg/m2 ) Ovarian volume (cm3 ) FSH (2.5 to 9.0 lU/L) LH (2.0 to 15.4 lU/L) T (0.7 to 2.8 nmol/L) E2 (90 to 440 pmol/L)
27.7 28.2 15.6 6.1 14.6 3.8 176.5
(26.0 to 29.4) (26.2 to 30.3) (14.2 to 17.1) (4.8 to 7.4) (12.5 to 16.7) (3.1 to 4.4) (131.9 to 221.1)
27.4 30.7 16.1 5.4 16.2 3.6 192.5
(25.7 to 29.2) (28.9 to 32.4) (14.5 to 17.7) (3.8 to 7.0) (14.8 to 17.7) (3.0 to 4.2) (160.8 to 224.2)
• Values are means with 95% CI in parentheses.
groups (Table 1). The number of treatment cycles were 68 in group A and 66 in group B. Human chorionic gonadotropin was administered in 44 and 59 cycles in the two groups, respectively. An LH surge was diagnosed in 18 cycles (26.5%) in group A patients, and accordingly no hCG was given. The rest of the cycles in both groups (8.8% and 10.6%, respectively) were suspended because of excessive or poor response. The number of ovulatory cycles as documented by disappearance of a leading follicle or appearance of a CL visualized ultrasonically after hCG injection or an LH surge in cycles that showed progressive rise in serum E2 during the induction period was 58 (85.3%) and 51 (77.3%) in the two groups, respectively. Table 2 shows the attributes of the ovulatory cycles in the two treatment groups. Patients in group A needed less hMG ampules per cycle (P < 0.001) with shorter induction time (P < 0.01) and had smaller leading follicles (P < 0.05). However, the midcycle serum LH and T values were not different between the two groups. Women treated with LHRH -a had more cycles with multiple dominant follicles (~15 mm) (35 of 51, 68.6%) compared with patients in group A (26 of 58, 44.8%) (x2 = 5.309, P < 0.05) and accordingly had higher midcycle Table 2
serum E2 level (P < 0.001). Moreover, they had higher luteal phase serum T (4.4 nmol/L [4.0 to 4.8], P < 0.001) and P (72.7 nmol/L [61.3 to 84.1], P < 0.01) values compared with patients in group A (3.3 nmol/L [3.2 to 3.5] and 50.3 nmol/L [46.2 to 54.4], respectively). The average increase in T value during the luteal phase was 1.1 nmol/L (1.0 to 1.2) in group A and 2.2 nmol/L (1.9 to 2.5) in group B (P < 0.001). Eighteen cycles (26.5%) in group A had a spontaneous LH surge; 16 of them were ovulatory (88.9%). They had a lower midcycle serum E 2 level than the other subgroup that received hCG, but the diameter of the leading follicle was not different between the two subgroups. However, the induction time, serum P, and the rise in serum T values during the luteal phase were lower in the first subgroup (Table 3). Seven women conceived in group A (43.8%) and 8 in group B (47.1%) (x2 = 0.0404, P > 0.05). The monthly fecundity rate per ovulatory cycle was 12.1% and 15.7%, respectively (x2 = 0.07203, P> 0.05). The six cycle cumulative PRs (14) were 41.2% and 49.9%, respectively. However, four women aborted after LH-RH-a + hMG medication (50.0%); three of them were midtrimester miscarriages, but only one of them was a multiple preg-
Biochemical and Biophysical Attributes During Ovulatory Cycles· Group A (n = 58) Dose/cycle (75 IU ampules) Induction time (d) Leading follicle (mm) Midcycle LH (lU/L) Midcycle T (nmol/L) Midcycle PRL (mlU/L) Midcycle E2 (pmol/L)
13.9 12.3 17.8 4.3 2.2 487.3 2,049.4
(13.4 to 14.3) (11.9 to 12.7) (17.5 to 18.1) (3.8 to 4.7) (2.1 to 2.4) (440.7 to 533.8) (1,775.2 to 2,323.7)
• Values are means with 95% CI in parentheses. b Group B was significantly different from group A (P < 0.001). C Group B was significantly different from group A (P < 0.01). Vol. 57, No.2, February 1992
GroupB (n = 51) 22.9 13.4 18.3 3.8 2.2 438.9 2,829.4
(21.6 to 24.2) b (12.8 to 13.9) c (18.0 to 18.7)d (3.2 to 4.3) (2.0 to 2.4) (395.5 to 482.5) (2,562.2 to 3,096.5)"
d Group B was significantly different from group A (P < 0.05) . " Group B was significantly different from group A (P < 0.001).
Abdel Gadir et al.
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311
Table 3
Characteristics of Ovulatory Cycles in Group A Patients· Cycles with LH surge Dose (75 IU ampules) Induction time (d) Leading follicle (mm) Midcycle E2 (pmol/L) Midcycle T (nmol/L) Luteal phase T (nmol/L) Rise in T (nmol/L) Luteal phase P (nmol/L)
13.6 11.4 17.3 1,498.0 2.3 3.1 0.9 43.4
(12.6 to 14.7) (11.0 to 11.8) (16.7 to 17.8) (949.0 to 2,047.0) (2.0 to 2.6) (2.9 to 3.4) (0.7 to 1.0) (36.7 to 50.1)
• Values are means with 95% CI in parentheses. b The two groups were significantly different (P < 0.01). C The two groups were significantly different (P < 0.001).
nancy (twins). One patient in group A aborted (Fisher's exact test = 0.1818). The multiple PR in group B was 25.0% (two sets of twins) and 14.3% in group A (one set of twins). The total multiple PR in the whole series was 20.0%. Studying the viable (n = 10) and nonviable (n = 5) pregnancies showed no difference between the two groups regarding age, BMI, ovarian volume, dose of hMG, induction time, midcycle E 2 , or the diameter of the leading follicles (P> 0.05). Interestingly, the luteal phase serum T values were higher in nonviable pregnancy cycles (5.5 nmol/L [2.6 to 8.3]) than in viable ones (3.7 nmol/L [2.6 to 4.8]) (P < 0.05). DISCUSSION
This is the first study that compared the effect of ovarian electrocautery versus an LH-RH-a on the response of patients with PCOD to hMG therapy. Previously, all patients in this series had failed to conceive after six treatment cycles with hMG. The hMG dose and induction time were significantly less in women pretreated with ovarian electrocautery than in group B. This is agreeable with the previous observation that women with PCOD had better response to CC therapy after ovarian electrocautery. This enhanced capability to respond to hMG may be because of a reduced intraovarian androgen concentration after ovarian electrocautery. It is interesting to note that the successful induction of ovulation and PRs were not significantly different between the two groups (P> 0.05). However, the abortion rate was three times more common in group B than in group A, yet the difference was not significant (P > 0.05). Nevertheless, the trend was evident. It is important to stress the point that despite a favorable endocrine milieu during the follicular phase, there were higher T values at the time of 312
Abdel Gadir et al.
Electrocautery versus desensitization
Cycles with hCG 14.0 12.7 18.0 2,259.5 2.2 3.4 1.2 52.9
(13.5 to 14.5) (12.2 to 13.1)b (17.6 to 18.4) (1,954.2 to 2,564.8)C (2.0 to 2.4) (3.2 to 3.6) (1.0 to 1.4)d (47.9 to 57.9)"
d The two groups were significantly different (P < 0.05) . "The two groups were significantly different (P < 0.05).
ovulation, fertilization, and nidation in group B patients. This may undo the favorable effect of the LH -RH -a incurred on the growing follicles during the follicular phase. This is especially so because T values were shown to be higher in nonviable than viable pregnancies. Moreover, the frequent booster hCG doses necessary to supplement the CL in group B patients may add to the hyperandrogenic state in this group. It may be necessary to reduce the dose of hCG given for the release of the oocyte and to use luteal phase P supplements instead of repeated hCG injections. Moreover, it is time to look for an alternative to hCG (with its long half-life) to promote the final maturation process of the oocyte and its release without stimulating the ovarian stroma with the resultant hyperandrogenic state in patients with PCOD. Alternatively, more patients could be treated with ovarian electrocautery because 26.5% of the cycl~s in group A had a spontaneous LH surge with lower luteal phase serum T values. More patients might have had such a surge if hCG was not given at an arbitrary follicular diameter of 18 mm. Furthermore, an LH surge may be stimulated after electrocautery + hMG using a bolus LH-RH injection or IN LH-RH spray (15). It can be concluded that ovarian electrocautery, done during a planned diagnostic laparoscopy, may be a better alternative to the more expensive LHRH-a for induction of ovulation in PCOD patients who do not conceive after gonadotropin therapy. Both medications were shown to give equivalent reduction in LH and T values previously (6) and an equivalent impact on the ovulation induction and PRs after hMG therapy during this study. However, the number of cycles with multiple dominant follicles, and, accordingly, the potential for hyperstimulation, the luteal phase serum T, and the abortion rate tend to be lower after ovarian electrocautery. Fertility and Sterility
REFERENCES 1. Gjiinnaess H. Polycystic ovarian syndrome treated by ovarian electrocautery through the laparascope. Fertil Steril1984;41: 20-5. 2. Greenblat E, Casper RF. Endocrine changes after laparoscopic ovarian cautery in polycystic ovarian syndrome. Am J Obstet GynecoI1987;156:279-85. 3. Van Der Weiden RM, Alberda AT. Laparoscopic ovarian electrocautery in patients with polycystic ovarian disease resistant to clomiphene citrate. Surg Endosc 1987;1:217-9. 4. Armar NA, McGarrigle HHG, Honour J, Holownia P, Jacobs HS, Lachelin GCL. Laparoscopic ovarian diathermy in the management of anovulatory infertility in women with polycystic ovaries: endocrine changes and clinical outcome. Fertil Steril 1990;53:45-9. 5. Fleming R, Haxton MJ, Hamilton MPR, Mc Cune GS, Black WP, Mac Naughton MC, et al. Successful treatment of infertile women with oligomenorrhoea using combination of a LHRH agonist and exogenous gonadotrophins. Br J Obstet Gynaecol 1985;92:369-74. 6. Abdel Gadir A, Khatim MS, Mowafi RS, Alnaser HMI, Alzaid HGN, Shaw RW. Hormonal changes in patients with polycystic ovarian disease after ovarian electrocautery or pituitary desensitization. Clin Endocrinol (OxO 1990;32:749-54. 7. Abdel Gadir A, Mowafi RS, Alnaser HMI, Alrashid AH, Alonezi OM, Shaw RW. Ovarian electrocautery versus human menopausal gonadotrophins and pure follicle stimulating hormone therapy in the treatment of patients with polycystic ovarian disease. Clin Endocrinol (OxO 1990;33:585-92. 8. Abdel Gadir A, Khatim MS, Mowafi RS, Alnaser HMI, Shaw RW. Endocrine changes following ovarian electrocautery in
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9.
10.
11.
12.
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15.
patients with polycystic ovarian syndrome. In: Shaw RW, editor. Polycystic ovaries: a disease or a symptom? advances in reproductive endocrinology, Vol. 3, Park Ridge, New Jersey: Parthenon Publishing Group, 1991:135-47. Fleming F. Induction of ovulation with a GnRH analogue and gonadotrophins in patients with polycystic ovarian disease. In: Brosens I, Jacobs HS, Runnenbaum B, editors. LHRH analogues in gynaecology. Carnforth, United Kingdom: The Parthenon Publishing Group, 1991:69-81. Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J 1986;293:355-9. Armitage P, Berry G. Statistical methods in medical research. Oxford, United Kingdom: Blackwell Scientific Publications, 1988. Campbell S, Goessens L, Goswamy R, Whitehead M. Real time ultrasonography for determination of ovarian morphology and volume. A possible early screening test for ovarian cancer? Lancet 1982;1:425-6. Brown JB. Gonadotrophins. In: Insler N, Lunenfeld B, editors. Infertility: male and female. Edinburgh, United Kingdom: Churchill Livingstone, 1986:359-96. Goldfarb AF, Schlaff S, Mansi ML. A life-table analysis of pregnancy yield in fixed low-dose menotropin therapy for patients in whom clomiphene citrate failed to induce ovulation. Fertil SteriI1982;37:639-44. Bentick B, Shaw RW, Hiland CA, Burford G, Bernard A. IVF pregnancy after induction of an ovulatory endogenous gonadotrophin surge using an LHRH agonist nasal spray. Hum Reprod 1990;5:570-2.
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FERTILITY AND STERILITY
Printed on acid-free paper in U.S.A.
Copyright to 1992 The American Fertility Society
The response of patients with polycystic ovarian disease to human menopausal gonadotropin therapy after ovarian electrocautery or a luteinizing hormone-releasing hormone agonist*
Ahmed Abdel Gadir, Ph.D.t:\: Huda M. I. Alnaser, M.B.Ch.B.§ Rawof S. Mowafi, M.D.§ Robert W. Shaw, M.D.II Faculty of Medicine and Maternity Hospital, Safat, Kuwait, and the Royal Free Hospital, London, United Kingdom
Objective: To compare the effect of ovarian electrocautery versus an intranasal (IN) luteinizing hormone-releasing hormone agonist (LH-RH-a) in the response of patients with polycystic ovarian disease (PCOD) to human menopausal gonadotropin (hMG) therapy. Design: A prospective study with serial randomization of patients in two groups for treatment with ovarian electrocautery + hMG or LH-RH-a + hMG. Setting: A teaching hospital reproductive endocrinology clinic. Patients: Thirty-three women with PCOD who failed to conceive after six treatment cycles with hMG. Main Outcome Measures: Midcycle and luteal phase endocrinology, ovulation, pregnancy rates (PRs), and miscarriage rates. Results: There was no difference in the ovulation or PRs between the two groups. However, the number of cycles with multiple dominant follicles, the luteal phase serum testosterone, and the miscarriage rate were lower in the group pretreated with ovarian electrocautery. Conclusions: Pretreatment of patients with PCOD with ovarian electrocautery may be a better alternative to IN LH-RH-a therapy for induction of ovulation with hMG. Fertil Steril1992;57:309-13 Key Words: Ovarian electrocautery, pituitary desensitization, induction of ovulation, polycystic ovarian disease
Laparoscopic ovarian electrocautery and luteinizing hormone-releasing hormone agonists (LH-RH-a) are alternative modalities used for induction of ovu-
Received August 12, 1991; revised and accepted October 23, 1991. * Supported by grants MO 024 and RMU 149 from the Central Research Unit, Kuwait University, Kuwait. t Academic Department of Obstetrics and Gynaecology, Faculty of Medicine, Kuwait University Health Science Center, Kuwait. :j: Reprint requests: A. Abdel Gadir, Ph.D., Academic Department of Obstetrics and Gynaecology, Royal Free Hospital, Pond Street, London NW3 2QG, United Kingdom. § Maternity Hospital. II Academic Department of Obstetrics and Gynaecology, The Royal Free Hospital. Vol. 57, No.2, February 1992
lation in patients with polycystic ovarian disease (peOD) not responsive to simpler medications (15). We have already shown that ovarian electrocautery caused reduction in the level of serum testosterone (T) and luteinizing hormone (LH) values equivalent to the changes that follQwed 8 weeks of intranasal (IN) buserelin acetate medication (Suprefact; Hoechst Pharmaceuticals, Frankfurt, Germany) in a dose of 800 ~g/d. However, there was a further advantage of increased follicle-stimulating hormone level (FSH) after ovarian electrocautery (6). We also showed that successful induction of ovulation, pregnancy rates (PRs), and abortion rates after ovarian electrocautery were equivalent to the corresponding rates that followed treatment with Abdel Gadir et al.
Electrocautery versus desensitization
309
human menopausal gonadotropin (hMG) and pure FSH (7). At the same time, there was improvement in the clinical response to clomiphene citrate (CC) therapy after ovarian electrocautery in patients who were initially nonresponsive. This may reflect the reduction in LH and T values and the increase in FSH level documented during hormone pulse analysis even in patients who did not ovulate after the procedure (8). On the other hand, combining LHRH-a with hMG therapy was shown to improve the PR in patients with PCOD as compared with hMG only (9). However, LH-RH-a therapy was not shown to reduce multiple follicular recruitment or the hyperstimulation rate. In this report, we compared the effect of laparoscopic ovarian electrocautery versus IN buserelin acetate medication on the response of patients with PCOD to hMG medication. MATERIALS AND METHODS Patients
Thirty-three women with PCOD consented to participate in the study. They had failed previously to conceive after six treatment cycles with hMG therapy. All patients were oligomenorrhoeic or amenorrhoeic with clinical or biochemical hyperandrogenization (T ~ 3 nmoljL), serum LH exceeding 10 lUlL, or a high LH:FSH ratio (>2:1), and in all cases ultrasonically visualized polycystic ovaries (10). All patients had normal prolactin (PRL), dehydroepiandrosterone sulfate, and 17ahydroxyprogesterone values. There was no other contributing factor to their infertility as verified by repeated investigations. All medications known to affect the hormonal milieu were suspended for 3 months before this study. Patients were divided at random into two groups with serial alternating entry after random allocation of the first case (11). Sixteen women were treated with ovarian electrocautery followed by hMG (group A) and 17 were treated with IN buserelin acetate and hMG (group B). Patients' age, body mass index (BMI in kg/m 2 ), and ovarian volume (12) were documented. An Aloka Echo Camera LS-Model SSD-248 ultrasonic machine with 3.5-MHz sector probe (Aloka Corporation, Tokyo, Japan) was used for monitoring ovulation using the full bladder technique. All women were examined laparoscopically with chromohydrotubation, and group A patients had ovarian electrocautery as described previously (6). This was followed by hMG therapy (Pergonal; Serono Laboratories, Rome, Italy) starting on the 3rd day after surgery. Treat310
Abdel Gadir et al.
Electrocautery versus desensitization
ment was started with one ampule (75 IU FSH and 75 IU LH), and the dose was decided individually for each patient as described previously (7). Blood samples were taken on the same day, 3rd, 7th, and 9th day after surgery, and as necessary thereafter and assessed for estradiol (E 2), FSH, LH, total T, and PRL. In the following cycles, the last effective dose used in the previous cycle was given as the starting dose on the 2nd day of menstruation. Blood samples were collected on the same day, 4th, 7th, and 9th days after starting hMG, and as necessary thereafter and assessed for the same hormones. The LH surge was diagnosed by examination of urine samples using Ovustick (Monoclonal Antibodies, Inc, Wheatley, Oxford, United Kingdom) done serially starting at follicular diameter of 14 mm or 2 days after the beginning of the cervical mucus biological shift (13) as reported by the patient and verified by the examiners. Human chorionic gonadotropin (hCG) (5,000 IU) was given at follicular diameter of 18 mm and serum E2 of 1,000 pmoljL per mature follicle (:::::15 mm). The hCG dose was not given if more than three mature follicles were seen and in cycles with a spontaneous LH surge. Blood samples were collected on the 3rd, 6th, and 9th days after hCG and assessed for serum progesterone (P), PRL, and T. Ultrasonic scan examinations were done on the same days to diagnose ovulation. Patients in group B were started on buserelin acetate IN medication immediately after diagnostic laparoscopy in a dose of 800 Jlg/d for 8 weeks. They were followed with weekly estimations of FSH, LH, E 2, and T to monitor response. Eight weeks later, they were started on hMG medication for induction of ovulation in the same pattern as for the first group. In addition, 2,000 IU of hCG were given every 3 days after the initial 5,000 IU dose to supplement the corpus luteum (CL) for a total of three doses. Buserelin acetate medication was continued throughout the whole study period. Treatment was offered for six cycles in both groups unless pregnancy occurred. All hormones were assayed in duplicates using radioimmunoassay as described previously (6, 7). Statistical analysis of the data was done using MannWhitney, X2 (after Yate's correction), and Fisher's exact tests when applicable. The Statistical Package for Social Studies Computer Programme (SPSSI PC+) was used for data analysis. Values are given as the mean with 95% confidence interval (CI). RESULTS
There were no differences in the pretreatment biophysical or endocrine criteria between the two Fertility and Sterility
Table 1
Biophysical and Hormonal Criteria of Patients Before Any Medication· Group B (n = 17)
Group A (n = 16) Age (y) BMI (kg/m2 ) Ovarian volume (cm3 ) FSH (2.5 to 9.0 lU/L) LH (2.0 to 15.4 lU/L) T (0.7 to 2.8 nmol/L) E2 (90 to 440 pmol/L)
27.7 28.2 15.6 6.1 14.6 3.8 176.5
(26.0 to 29.4) (26.2 to 30.3) (14.2 to 17.1) (4.8 to 7.4) (12.5 to 16.7) (3.1 to 4.4) (131.9 to 221.1)
27.4 30.7 16.1 5.4 16.2 3.6 192.5
(25.7 to 29.2) (28.9 to 32.4) (14.5 to 17.7) (3.8 to 7.0) (14.8 to 17.7) (3.0 to 4.2) (160.8 to 224.2)
• Values are means with 95% CI in parentheses.
groups (Table 1). The number of treatment cycles were 68 in group A and 66 in group B. Human chorionic gonadotropin was administered in 44 and 59 cycles in the two groups, respectively. An LH surge was diagnosed in 18 cycles (26.5%) in group A patients, and accordingly no hCG was given. The rest of the cycles in both groups (8.8% and 10.6%, respectively) were suspended because of excessive or poor response. The number of ovulatory cycles as documented by disappearance of a leading follicle or appearance of a CL visualized ultrasonically after hCG injection or an LH surge in cycles that showed progressive rise in serum E2 during the induction period was 58 (85.3%) and 51 (77.3%) in the two groups, respectively. Table 2 shows the attributes of the ovulatory cycles in the two treatment groups. Patients in group A needed less hMG ampules per cycle (P < 0.001) with shorter induction time (P < 0.01) and had smaller leading follicles (P < 0.05). However, the midcycle serum LH and T values were not different between the two groups. Women treated with LHRH -a had more cycles with multiple dominant follicles (~15 mm) (35 of 51, 68.6%) compared with patients in group A (26 of 58, 44.8%) (x2 = 5.309, P < 0.05) and accordingly had higher midcycle Table 2
serum E2 level (P < 0.001). Moreover, they had higher luteal phase serum T (4.4 nmol/L [4.0 to 4.8], P < 0.001) and P (72.7 nmol/L [61.3 to 84.1], P < 0.01) values compared with patients in group A (3.3 nmol/L [3.2 to 3.5] and 50.3 nmol/L [46.2 to 54.4], respectively). The average increase in T value during the luteal phase was 1.1 nmol/L (1.0 to 1.2) in group A and 2.2 nmol/L (1.9 to 2.5) in group B (P < 0.001). Eighteen cycles (26.5%) in group A had a spontaneous LH surge; 16 of them were ovulatory (88.9%). They had a lower midcycle serum E 2 level than the other subgroup that received hCG, but the diameter of the leading follicle was not different between the two subgroups. However, the induction time, serum P, and the rise in serum T values during the luteal phase were lower in the first subgroup (Table 3). Seven women conceived in group A (43.8%) and 8 in group B (47.1%) (x2 = 0.0404, P > 0.05). The monthly fecundity rate per ovulatory cycle was 12.1% and 15.7%, respectively (x2 = 0.07203, P> 0.05). The six cycle cumulative PRs (14) were 41.2% and 49.9%, respectively. However, four women aborted after LH-RH-a + hMG medication (50.0%); three of them were midtrimester miscarriages, but only one of them was a multiple preg-
Biochemical and Biophysical Attributes During Ovulatory Cycles· Group A (n = 58) Dose/cycle (75 IU ampules) Induction time (d) Leading follicle (mm) Midcycle LH (lU/L) Midcycle T (nmol/L) Midcycle PRL (mlU/L) Midcycle E2 (pmol/L)
13.9 12.3 17.8 4.3 2.2 487.3 2,049.4
(13.4 to 14.3) (11.9 to 12.7) (17.5 to 18.1) (3.8 to 4.7) (2.1 to 2.4) (440.7 to 533.8) (1,775.2 to 2,323.7)
• Values are means with 95% CI in parentheses. b Group B was significantly different from group A (P < 0.001). C Group B was significantly different from group A (P < 0.01). Vol. 57, No.2, February 1992
GroupB (n = 51) 22.9 13.4 18.3 3.8 2.2 438.9 2,829.4
(21.6 to 24.2) b (12.8 to 13.9) c (18.0 to 18.7)d (3.2 to 4.3) (2.0 to 2.4) (395.5 to 482.5) (2,562.2 to 3,096.5)"
d Group B was significantly different from group A (P < 0.05) . " Group B was significantly different from group A (P < 0.001).
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Table 3
Characteristics of Ovulatory Cycles in Group A Patients· Cycles with LH surge Dose (75 IU ampules) Induction time (d) Leading follicle (mm) Midcycle E2 (pmol/L) Midcycle T (nmol/L) Luteal phase T (nmol/L) Rise in T (nmol/L) Luteal phase P (nmol/L)
13.6 11.4 17.3 1,498.0 2.3 3.1 0.9 43.4
(12.6 to 14.7) (11.0 to 11.8) (16.7 to 17.8) (949.0 to 2,047.0) (2.0 to 2.6) (2.9 to 3.4) (0.7 to 1.0) (36.7 to 50.1)
• Values are means with 95% CI in parentheses. b The two groups were significantly different (P < 0.01). C The two groups were significantly different (P < 0.001).
nancy (twins). One patient in group A aborted (Fisher's exact test = 0.1818). The multiple PR in group B was 25.0% (two sets of twins) and 14.3% in group A (one set of twins). The total multiple PR in the whole series was 20.0%. Studying the viable (n = 10) and nonviable (n = 5) pregnancies showed no difference between the two groups regarding age, BMI, ovarian volume, dose of hMG, induction time, midcycle E 2 , or the diameter of the leading follicles (P> 0.05). Interestingly, the luteal phase serum T values were higher in nonviable pregnancy cycles (5.5 nmol/L [2.6 to 8.3]) than in viable ones (3.7 nmol/L [2.6 to 4.8]) (P < 0.05). DISCUSSION
This is the first study that compared the effect of ovarian electrocautery versus an LH-RH-a on the response of patients with PCOD to hMG therapy. Previously, all patients in this series had failed to conceive after six treatment cycles with hMG. The hMG dose and induction time were significantly less in women pretreated with ovarian electrocautery than in group B. This is agreeable with the previous observation that women with PCOD had better response to CC therapy after ovarian electrocautery. This enhanced capability to respond to hMG may be because of a reduced intraovarian androgen concentration after ovarian electrocautery. It is interesting to note that the successful induction of ovulation and PRs were not significantly different between the two groups (P> 0.05). However, the abortion rate was three times more common in group B than in group A, yet the difference was not significant (P > 0.05). Nevertheless, the trend was evident. It is important to stress the point that despite a favorable endocrine milieu during the follicular phase, there were higher T values at the time of 312
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Cycles with hCG 14.0 12.7 18.0 2,259.5 2.2 3.4 1.2 52.9
(13.5 to 14.5) (12.2 to 13.1)b (17.6 to 18.4) (1,954.2 to 2,564.8)C (2.0 to 2.4) (3.2 to 3.6) (1.0 to 1.4)d (47.9 to 57.9)"
d The two groups were significantly different (P < 0.05) . "The two groups were significantly different (P < 0.05).
ovulation, fertilization, and nidation in group B patients. This may undo the favorable effect of the LH -RH -a incurred on the growing follicles during the follicular phase. This is especially so because T values were shown to be higher in nonviable than viable pregnancies. Moreover, the frequent booster hCG doses necessary to supplement the CL in group B patients may add to the hyperandrogenic state in this group. It may be necessary to reduce the dose of hCG given for the release of the oocyte and to use luteal phase P supplements instead of repeated hCG injections. Moreover, it is time to look for an alternative to hCG (with its long half-life) to promote the final maturation process of the oocyte and its release without stimulating the ovarian stroma with the resultant hyperandrogenic state in patients with PCOD. Alternatively, more patients could be treated with ovarian electrocautery because 26.5% of the cycl~s in group A had a spontaneous LH surge with lower luteal phase serum T values. More patients might have had such a surge if hCG was not given at an arbitrary follicular diameter of 18 mm. Furthermore, an LH surge may be stimulated after electrocautery + hMG using a bolus LH-RH injection or IN LH-RH spray (15). It can be concluded that ovarian electrocautery, done during a planned diagnostic laparoscopy, may be a better alternative to the more expensive LHRH-a for induction of ovulation in PCOD patients who do not conceive after gonadotropin therapy. Both medications were shown to give equivalent reduction in LH and T values previously (6) and an equivalent impact on the ovulation induction and PRs after hMG therapy during this study. However, the number of cycles with multiple dominant follicles, and, accordingly, the potential for hyperstimulation, the luteal phase serum T, and the abortion rate tend to be lower after ovarian electrocautery. Fertility and Sterility
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