by Falope-rings* or Filshie-clipst*

FERTILITY AND STERILITY Copyright 0 1992 The American Fertility Society Printed on acid-free paper in U.S.A. Hormonal and menstrual changes after laparoscopic sterilization by Falope-rings* or Filshie-clipst* Ingrid Thranov, M.D. 1111 Jens B. Hertz, M.D. II Jens J0rgen Kjer, M.D.** Anne Andresen, M.D. ** Snezana Micic, M.Sc. tt Jan Nielsen, M.D.tt S0ren Hancke, M.D.+:!: Gentofte County Hospital, Rigshospitalet, Statens Seruminstitute, Copenhagen, Denmark Objective: To evaluate the influence oflaparoscopic sterilization by Falope-rings (Cabot Medical Corp., Langhorne, PA) or Filshie-clips (Femcare, Nottingham, United Kingdom) on menstrual pattern and ovulatory function. Design: A prospective, nonrandomized study of women sterilized by Falope-rings (n = 6) or Filshie-clips (n = 5). Menstrual charts were kept. Serum follicle-stimulating hormone (FSH), estradiol (E 2 ) and progesterone (P) were measured by means of radioimmunoassay in one cycle before and 3, 6, and 12 months after the sterilization. Blood samples were drawn on day -6, -2, 0, +6, + 10 of the menstrual cycle, ovulation corresponding to day O. The women sterilized by Filshie-clips had abdominal ultrasonography of the ovaries measuring the leading follicle on day -6, -2, 0, +6 of the menstrual cycle. Patients: Twelve women, 25 to 38 years old, with regular menstrual cycles and no use of oral contraceptives or intrauterine contraceptive device at least 6 months before sterilization. One woman was excluded. Results: After the sterilization, all women reported unchanged menstrual pattern. The follicular rise in E2 unchanged, and FSH levels fell accordingly. Progesterone levels were ovulatory, but the midluteal P peak 3 months poststerilization was significantly decreased. Serial abdominal ultrasonography in women sterilized by Filshie-clips confirmed ovulation in all cycles except in one woman, who had an unruptured follicle in one cycle before and in the sixth cycle after sterilization. Conclusion: Laparoscopic sterilization by Falope-rings or Filshie-clips does not seem to interfere with menstrual pattern or ovulatory function. Fertil Steril1992;57:751-5 Key Words: Laparoscopic sterilization, menstrual pattern, ovulatory function, prospective, longitudinal Received April 15, 1991; revised and accepted December 31, 1991. * Falope-rings, Cabot Medical Corp., Langhorne, Pennsylvania. t Filshie-clips, Femcare LTD, Nottingham, United Kingdom. t Supported by grant number 5.29.01.20. from the Danish Medical Council, H.C. Andersens Boulevard, Copenhagen, Denmark. Presented at the 7th World Congress of Human Reproduction, Helsinki, Finland, June 29, 1990. II Department of Obstetrics and Gynecology, Gentofte County Hospital. 11 Reprint requests: Ingrid Thranov, Vejlesl!lvej 30, DK-2840 Holte, Denmark. ** Department of Obstetrics and Gynecology, Rigshospitalet. tt Statens Seruminstitut. tt Ultrasound Laboratory, Gentofte County Hospital. Female sterilization is an effective contraceptive method that has gained in popularity all over the world. In several descriptive studies as reviewed by Rioux (1), female sterilization has been associated with sequelae such as menstrual irregularities, dysmenorrhoea, and early menopausal symptoms. However, many of these studies suffer from meth- 0dological problems such as retrospective study design, lack of control groups, no consideration of age, parity, or earlier contraceptive use, and the studies have focused on aggravation of the studied variables and not on improvements. In prospective longitudinal descriptive studies of sterilized women, menstrual changes have not been found (2, 3). Thranov et ai. Laparoscopic sterilization 751

f Poststerilization endocrine changes have been described among women who have undergone surgical sterilization, e.g., low serum-progesterone (P) levels during the luteal phase (4-6), low preovulatory serum estradiol (E 2 ) peak (7) and high midluteal serum E2 (5). For comparison, women belonging to a similar population were used as control groups. In studies in which the sterilized women have been used as their own control, however, the above mentioned menstrual and endocrine changes have not been confirmed (8, 9). The purpose of the present study was to evaluate prospectively the influence of laparoscopic female sterilization by the Falope-ring (Cabot Medical Corp., Langhorne, PA) orthe Filshie-clip technique (Femcare LTD, Nottingham, United Kingdom) on the menstrual pattern and ovarian function in a selected group of women using their presterilization parameters as control. The influence of these sterilization techniques on the menstrual pattern, the ovarian endocrine function, and the ovulatory function followed by ultrasonography have not been investigated concurrently before. MATERIALS AND METHODS Twelve women referred to sterilization at the Departments of Obstetrics and Gynecology at Gentofte County Hospital (Filshie-clips, n = 6) and Rigshospitalet, Copenhagen, Denmark (Falope-rings, n = 6) gave written informed consent to participate in the study. The study was accepted by the local ethical committee. The women had to fulfill the following criteria: (1) age 25 to 38 years old; (2) parity;;::: 1, ovulation not induced; (3) regular menstrual cycles the past 6 months with a cycle length between 21 and 35 days; (4) no use of hormonal contraceptives or hormonal treatment the past 6 months; (5) no use of intrauterine contraceptive device (IUD) the past 6 months; (6) no prior liver disease; (7) normal weight (±15% of ideal body weight, according to the Geigy table); (8) no prior gynecological diseases or gynecological surgery; and (9) no use of medicine, no alcohol or medicine abuse. One woman did not return for follow-up after sterilization and was consequently excluded from the study. The sterilizations were performed laparoscopically using the two puncture technique either by Faloperings (n = 6) or Filshie-clips (n = 5). The patients were all sterilized in the follicular phase, thus avoiding a concurrent dilatation and curettage. Prospectively, starting 1 month before the sterilization, the women registered the cycle length and the length of their periods, graded their menstrual flow each day (strong, moderate, slight, spotting) and registered intermenstrual bleedings and dysmenorrhea. The women sterilized by Filshie-clips kept temperature charts during the studied menstrual periods. Blood was drawn for follicule-stimulating hormone (FSH), E 2, and P determination on day -6, -2, 0, +6, + 10, where day was the expected day of ovulation. These measurements were carried out during one period immediately before the sterilization and 3, 6, and 12 months after the sterilization. All serum specimens were immediately frozen at -20 C, and all the analyses were performed in the same batch at the Hormonal Department, Statens Seruminstitut, Copenhagen at the end of the study. The analyses were performed by specific radioimmunoassays, FSH with an interassay coefficient of variation (CV) on approximately 6%, E2 and P with an interassay CV on approximately 7% and 8%, respectively. In women sterilized by Filshie-clips, the menstrual and hormonal parameters were registered in two subsequent cycles immediately before the sterilization. Furthermore, the size of the leading follicle was measured by serial abdominal ultrasonography performed on menstrual days -6, -2, 0, +6. The examinations were carried out using a 3.5-MHz sector scanner with the full bladder technique, and the internal diameter of the leading follicle was measured. The ultrasonography was performed in two subsequent cycles before and in cycle 3, 6, and 12 after the sterilization. For statistical analysis the paired t-test and the Mann-Whitney rank sum test were used. The level for statistical significance was P < 0.05. RESULTS Hormonal parameters from the women sterilized by Falope-rings and Filshie-clips were statistically evaluated separately and together using the hormonal parameters from 1 month before the sterilization for comparison. The profiles of the included patients are shown in Table 1. The women sterilized by Falope-rings were significantly older than the women sterilized by Filshie-clips, with a mean of 35 years and 31 years, respectively. None of the 11 women reported changes in cycle length, menstrual flow, or length of bleeding period after the sterilization. Mean cycle length and SD after the sterilization was calculated during the 1 year follow-up for nine of the women. All women 752 Thranov et al. Laparoscopic sterilization Fertility and Sterility

Table 1 Presterilization Data of Six Women Sterilized by Falope ring Technique and Five Women Sterilized by Filshie clip Technique Patients Age Menstrual pattern length of cycle/ period Pariety Weight/height Falope rings 1 36 2 29 3 35 4 36 5 38 6 36 Filshie-clips 7 27 8 34 9 31 10 28 11 35 y did kglem 25/6 3 68/171 30/6 2 72/168 30/7 2 46/161 30/8 2 57/164 28/6 2 56/156 31/6 2 75/171 26/7 2 55/159 30/6 2 60/170 30/7 2 60/165 28/4 1 65/173 30/5 2 60/167 had the same mean period interval as reported by themselves before the sterilization with an SD of 1.5 to 3.4 days. None of the sterilized women developed persistent dysmenorrhea. Three women reported transient dysmenorrhea at the first period after the sterilization. None of the 11 women developed menopausal symptoms or intermenstrual bleedings during the 1 year follow-up; three women reported modest abdominal pain at the time of ovulation. The results of the hormonal tests from all 11 women are shown in Table 2. As noted in the Table the number of women included varied in the control Table 2 Hormonal Parameters 1 Months Before and 3, 6, and 12 Months After Sterilization by Falope-rings or Filshie-clips Time from FSH Luteal E2 sterilization E2peak peak peak Ppeak mo pmolll lull pmolll nmolll -1 911 ± 386* 8.2 ± 4.6 517±174 57 ± 10.0 +3 808 ± 250 6.3 ± 2.4 513 ± 143 45 ± 18.5 No. 10 10 10 10 tt 0.91 1.30 0.46 2.69 Probability 0.193 0.113 0.328 0.012+ -1 861 ± 312 8.3 ± 4.5 506 ± 166 57 ± 11.5 +6 975 ± 447 7.8 ± 2.9 500 ± 157 54 ± 16.7 No. 10 10 10 8 tt -0.64 0.52 0.48 0.91 Probability 0.731 0.308 0.321 0.197-1 953 ± 404 7.7 ± 4.4 491 ± 150 55 ± 12.0 +12 786 ± 277 7.6 ± 4.0 425 ± 137 43 ± 23.8 No. 9 9 8 7 tt 1.08 0.07 1.22 1.7 Probability 0.156 0.473 0.131 0.066 * Values are means ± SD. t Paired sample t-test. + Significant P < 0.05. periods. Among the women sterilized by Faloperings, one woman missed the 3-month control, one woman missed the 6-month control, and two women missed the 12-month control. Because of lack of serum, P could not be measured at the 6-month control in 2 women (1 Falope-rings and 1 Filshie-clips) and at 12 months for 1 woman (Filshie-clips). No woman missed more than one control. To use the paired t-test for comparison, the hormonal values of the missing cases were omitted from the reference month and thus the mean value of the reference month (-1) varies. Peak serum P was within normal limits for an ovulatory cycle in all women before as well as after the sterilization (Fig. 1). However, there was a sig- PROGESTERONE PEAK -2 +3 +6 + 12 TIME FROM STERILIZATION (MONTHS) Figure 1 Peak serum P before and after sterilization. Shaded area represents the reference range for ovulatory levels. Thranov et al. Laparoscopic sterilization 753

r nificant fall in peak serum P 3 months after the sterilization and a borderline significant drop at 12 months. The five women sterilized by Filshie-clips had hormonal parameters available from the 2 months preceding the sterilization. The mean peak P values were 49 nmoljl and 57 nmoljl, respectively, (t = 1.57, P = 0.09). The results did not differ, when the hormonal parameters from the women sterilized by Falope-rings and the women sterilized by Filshie-clips were analyzed separately. Abdominal ultrasonography of the women sterilized by Filshie-clips measuring the internal diameter of the leading follicle demonstrated normal ovulation in all women but one. This woman demonstrated an unruptured follicle during one period before and 6 months after the sterilization (Fig. 2). The mean size of the leading follicle was unaffected by the sterilization. Luteal phase length according to temperature charts were > 11 days except in one woman who had a luteal phase of 9 and 12 days before, and 10,14, and 12 days after the sterilization. DISCUSSION In the present study, six women sterilized by Falope-rings and five women sterilized by Filshie-clips were followed 1 or 2 months, respectively, before sterilization and at 3, 6, and 12 months after sterilization by menstrual registrations, measurement of hormonal parameters, and the five women sterilized by Filshie-clips had abdominal ultrasonography of the ovaries following the size of the leading follicle. In an attempt to avoid the confounding factors of earlier studies, we have focused on healthy, young, fertile women who did not use hormonal contraceptives or IUD before sterilization. The women did not report menstrual changes induced by the sterilization. This finding is in accordance with a prospective multicenter study by Bhiwandiwhala et al. (2) of 6,128 women who had undergone laparoscopic sterilization. The majority of the women did not have menstrual changes (cycle length, duration, and amount of menstrual flow) at 12 months follow-up. A small number of women did experience a change. However, their study did not control for previous use of contraceptives. The analysis of our hormonal data before and after sterilization confirmed normal ovulatory function after the sterilization (Table 2 and Fig. 1). When dealing with the P data in this study, it has to be taken into consideration that we only measured serum P twice in the luteal phase, i.e., the 6th and the 10th day after the calculated day of ovulation. MM 30 20 10 SIZE OF LEADING FOLLICLE o ' BEFORE STERILIZAnON : 3 MONTHS AFTER STER. A : 6 MONTHS AFTER STER. ~-=" -6-4 -2 o +2 +4 +6 +8 +10 DAY OF THE MENSTRUAL CYCLE Figure 2 Size of leading follicle measured during five menstrual cycles demonstrating two cycles with luteinized unruptured follicle, one cycle before and one cycle after sterilization, in a woman sterilized by Filshie-clips. In doing so, we found a significant fall in the luteal peak serum P 3 months after the sterilization and a borderline significant fall after 12 months. The significance of this finding is difficult to interpret. The P secretion in the midluteal and late luteal phase is pulsatile, which results in a wide daily fluctuation in the serum P levels. In a recent review article of luteal phase deficiency (LPD) (10), it was concluded that the use of a single or a few selected serum determinations to accurately diagnose LPD is problematic, secondary to inherent sampling variability. The significant drop in peak serum P found in this study could thus be incidental. Supporting this theory was the finding of a similar fluctuation in the peak serum P observed among the women whose hormonal parameters were measured in 2 consecutive months before sterilization. Alvarez et al. (9) used a similar study design as ours applied on women sterilized by the Pomeroy or the Uchida technique. The luteal phase before and after sterilization was evaluated by comparing the midluteal P, defined as the sum of three values from samples taken every other day since day 5 and through day 10 after the luteinizing hormone peak. They found a significant increase in midluteal P 2 months after the sterilization, and they interpreted this increase as a chance event. Other ways to evaluate possible LPD includes length of luteal phase, measurement of leading follicle, and endometrial biopsy. The women sterilized by Filshie-clips were followed by temperature charts and serial ultrasonography, and neither examinations indicated LPD. We did not perform endometrial biopsies. In a study by Donnez et al. (4) comparing women sterilized by tubal ligation or electrocoagulation with women sterilized by Hulka Clements clips (4) and a nonsterilized control group, the mean midluteal P 754 Thranov et al. Laparoscopic sterilization Fertility and Sterility

was found to be significantly lower among the women sterilized by tubal ligation or electrocoagulation. They also performed endometrial biopsies, which more frequently showed retarded endometrium in the tubal ligation or electrocoagulation group. They concluded, however, that there was a poor correlation between retarded endometrium and P levels. Sixty percent of the women who choose sterilization state contraceptive problems as their main reason for seeking sterilization (11). Thus, sterilized women comprise a group of women who have had gynecological problems before the sterilization. This may explain why our study group of young healthy sterilized women did not confirm reports of sterilization side effects. The ideal women for sterilization as used in this study are rarely encountered in the medical practice. The 12 women enrolled in this study comprised 10% of the women between 25 and 38 years old applying for sterilization at our institutions during the study period. Comparing women with themselves before and after sterilization introduces the variable of time, but this seems preferable to accepting the many variables inherent in selecting an alternative control group. For example, in some studies of sterilization side effects, wives of vasectomized men have been used as control group (12). According to a study comparing these two groups of women (11), sterilized women more often experienced contraceptive side effects and failures compared with wives of vasectomized men. In conclusion this study has shown that laparoscopic sterilization by Falope-rings or Filshie-clips does not seem to interfere with ovulatory function or menstrual pattern in healthy young women. Ackrwwledgment. We thank statistician Mette Madsen, Danish Institute of Clinical Epidemiology, Copenhagen, for statistical advice and Birgit Svenstrup, M.Sc., Serum Institutet, Copenhagen for coordinating the hormone analysis. REFERENCES 1. Rioux J -E. Late complications offemale sterilization: a review of the literature and a proposal for further research. J Reprod Med 1977;19:329-40. 2. Bhiwandiwala PP, Mumford SD, Feldhlum PJ. A comparison of different laparoscopic sterilization occlusion techniques in 24,439 procedures. Am J Obstet GynecoI1982;144:319-31. 3. Rivera R, Gaitan JR, Ruiz R, Hurley DP, Arenas M, Flores C, et al. Menstrual patterns and progesterone circulating levels following different procedures of tubal occlusion. Contraception 1989;40:157-69. 4. Donnez J, Wauter M, Thomas K. Luteal function after tubal sterilization. Obstet Gynecol 1981;57:65-8. 5. Hargrove JT, Abraham GE. Endocrine profile of patients with post-tubal-ligation syndrome. J Reprod Med 1981;26: 359-62. 6. Radwanska E, Headley SK, Dmowski P. Evaluation of ovarian function after tubal sterilization. J Reprod Med 1982;27: 376-84. 7. Cattanach J. Oestrogen deficiency after tubal ligation. Lancet 1985;1(8433):847-9. 8. Helm G, Sj0berg NO. Progesterone levels before and after laparoscopic tubal sterilization using endotherm coagulation. Acta Obstet Gynecol Scand 1983;62:63-6. 9. Alvarez F, Faundes A, Brache V, Tejada AS, Segal S. Prospective study of the pituitary-ovarian function after tubal sterilization by the Pomeroy or Uchida techniques. Fertil Steril 1989;51:604-8. 10. McNeely MJ, Soules MR. The diagnosis of luteal phase deficiency: a critical review. Fertil Steril1988;50:1-15. 11. Kjersgaard AG, Thranov I, Rasmussen OV, Hertz J. Male or female sterilization: a comparative study. Fertil SteriI1989;51: 439-43. 12. DeStefano F, Perlman JA, Peterson HB, Diamond EL. Longterm risk of menstrual disturbances after tubal sterilization. Am J Obstet Gynecol 1985;152:835-41. Thranov et ai. Laparoscopic sterilization 755