A prospective study comparing unilateral and bilateral laparoscopic ovarian diathermy in women with the polycystic ovary syndrome

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1 FERTILITY AND STERILITY Copyright " 1994 The American Fertility Society Vol. 62, No.5, November 1994 Printed on acid-free paper in U. S. A. A prospective study comparing unilateral and bilateral laparoscopic ovarian diathermy in women with the polycystic ovary syndrome Adam H. Balen, M.R.C.O.G.* Howard S. Jacobs, M.D. Department of Reproductive Endocrinology, University College London and Middlesex Hospital Medical School, London, United Kingdom Object: To assess the efficacy of unilaterallaparoscopic ovarian diathermy in the induction of ovulation in anti-estrogen-resistant polycystic ovary syndrome (PCOS). Design: A prospective randomized study was performed to compare unilateral with bilateral ovarian diathermy. Setting: Specialist Reproductive Endocrine Unit. Patients: Ten patients with anti-estrogen-resistant PCOS. Interventions: Randomization to unilateral (4 patients) or bilaterallaparoscopic ovarian diathermy (6 patients). Main outcome measures: Rate and side of ovulation and change in endocrine profiles after ovarian diathermy. Results: Unilateral ovarian diathermy resulted in ovulation from both ovaries. Fifty percent of the patients responded to diathermy and those who responded had a significantly greater fall in serum LH concentrations than those who failed to respond. Conclusions: The mechanism of action of laparoscopic ovarian diathermy is via a correction of disturbed ovarian-pituitary feedback. Hypersecretion of LH appears to be the most significant endocrine disturbance in these patients. Fertil Steril 1994;62:921-5 Key Words: Polycystic ovary syndrome, unilaterallaparoscopic ovarian diathermy, luteinizing hormone Laparoscopic ovarian diathermy is a successful form of ovulation induction for women with antiestrogen-resistant polycystic ovary syndrome (PCOS) (1, 2). Not only is ovulation induced but endocrine abnormalities, such as hypersecretion of LH, are corrected. It appears that injury to the ovaries triggers ovulation, presumably through an alteration of ovarian-pituitary feedback, which is disturbed in patients with infertility secondary to the Received January 10, 1994; revised and accepted May 27, * Reprint requests and present address: Adam H. Balen, M.R.C.O.G., Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford, United Kingdom OX3 9DU (FAX: ). PCOS (3). The precise mechanism is, however, unclear. We performed a prospective study to compare unilateral with bilateral ovarian diathermy to observe which ovary responded by ovulating. If only the treated ovary ovulated after unilateral diathermy, it would suggest that diathermy induced ovulation by a direct effect on the ovary. On the other hand, if the nontreated ovary ovulated, it would suggest that the treatment works via an endocrine effect, presumably on ovarian-pituitary feedback. MATERIALS AND METHODS Ten women with anovulatory infertility caused by clomiphene citrate (CC)-resistant PCOS were Vol. 62, No.5, November 1994 Balen and Jacobs Unilaterallaparoscopic ovarian diathermy 921

2 Table 1 Baseline Characteristics of 10 Patients Undergoing Laparoscopic Ovarian Diathermy* Age (y) Years of infertility BMit (kg/m 2 ; [19 to 25]):j: FSH IU/L (1 to 10):j: LH IU/L (1 to 10):j: T (nmoljl; [0.5 to 2.5]):j: *Values are means± SD; range in parentheses. t BMI, body mass index. :j: Normal range ± 2.3 (27 to 33) 5.6 ± 1.3 (4 to 8) 23.2 ± 3.1 (19.1 to 29.4) 6.1 ± 1.8 (3.5 to 9.2) 14.1 ± 5.5 (5.7 to 25) 2. 7 ± 1.6 (0.5 to 5.3) randomly allocated to either unilateral or bilateral laparoscopic ovarian diathermy. They gave informed consent to the study, which had been approved by the hospital Clinical Investigations Panel. The clinical characteristics of the patients are recorded in Table 1. The methods of hormone measurements have been reported previously (4). All of the women had oligomenorrhoea and were nulligravid. All had normal serum PRL concentrations and normal thyroid function (data not shown). They had all been assessed laparoscopically by their local gynecologist before referral and were reported to have patent fallopian tubes. Two patients, however, were then found to have pelvic adhesions and one blocked tube each at the time of the laparoscopic ovarian diathermy procedure. One patient had a bicornuate uterus. The partners of three of the patients had severe oligospermia or azoospermia, and therefore additional fertility treatment by donor insemination was required. All of the patients had been unresponsive to treatment with CC (i.e., anovulatory) in doses up to 100 mg/d for 5 days; four had also failed to respond to tamoxifen, and five had been treated with gonadotropins and either overstimulated or had failed to ovulate. Failure of ovulation had been confirmed by a combination of ultrasound (US) scans and low luteal phase serum concentrations of P. In addition, eight of the patients had elevated basal serum concentrations of LH. The two patients with normal pre-laparoscopic ovarian diathermy serum LH concentrations were referred for laparoscopic ovarian diathermy as they had persistently formed cysts in response to both CC and gonadotropin therapy. Of the 10 patients, 6 received bilateral laparoscopic ovarian diathermy and 4 had unilateral diathermy, 3 to the right and 1 to the left ovary. Ovarian diathermy was performed using the technique described by Armar et al. (5). Laparoscopy was performed under general anesthesia. The pelvic organs were inspected and tubal patency confirmed by transcervical injection of methylene blue dye. About 300 ml of normal saline was instilled into the Pouch of Douglas via a suprapubic V erres needle. The ovary was lifted onto the anterior wall of the uterus, where it was diathermized at four points, with the diathermy setting on 4 ( 40 W) for 4 seconds at each point. A specially designed diathermy probe was used (5). The probe has a springloaded central spike projecting 8 mm into the ovary from an insulated handle. The ovary was cooled in the pool of saline both to minimize adhesion formation and to prevent heat trauma to adjacent viscera. The saline was left in the peritoneal cavity at the end of the procedure. Blood samples were taken from the patients on the day of the operation and at weekly to fortnightly intervals thereafter. For each patient all of the blood samples were taken at the same time of the day. Pelvic ultrasonography was also performed at each visit to the clinic. The US department was not informed of which ovary/ovaries had been treated. RESULTS Five patients (50%) ovulated within 6 weeks of laparoscopic ovarian diathermy but the remaining five failed to ovulate by 12 weeks. Three of the four patients who received unilateral diathermy ovulated, all from the contralateral ovary in the first cycle and then alternately from each ovary. Two of the six patients who had bilateral laparoscopic ovarian diathermy ovulated. The mean pretreatment and post-treatment LH, FSH, and T concentrations are recorded in Table 2 and those of nonresponders are compared with the responders (irrespective of whether they had unilateral or bilateral laparoscopic ovarian diathermy). The pre- Table 2 Pretreatment and Post-treatment Serum Hormone Concentrations in Responders and Nonresponders* Pretreatment Post-treatment % Change LH Responders 13.9 ± ± ± 9.4 N onresponders 14.9 ± ± ± 29.9 FSH Responders 5.5 ± ± ± 17.9 N onresponders 6.6 ± ± ± 61.1 T Responders 2.3 ± ± ± 23.2 N onresponders 3.9 ± ± ± 18.4 *Values are means± SD. 922 Balen and Jacobs Unilaterallaparoscopic ovarian diathermy Fertility and Sterility

3 treatment values are a mean of at least two measurements and the post-treatment values are a mean of at least six measurements. There were no significant differences between the hormone measurements of the responders and those of the nonresponders. When the pretreatment and post-treatment values were compared, there were no differences in the serum FSH and T concentrations in either the responders or the nonresponders. In the responders, however, there was a significant fall of the serum LH concentration after laparoscopic ovarian diathermy (P = 0.045; 95% CI, 0.2 to 13.4), whereas in the nonresponders there was no difference in the LH concentrations before and after treatment. None of the patients conceived as a result of the ovarian diathermy. The three patients who responded to unilateral diathermy ovulated for 4 to 6 months. One required donor insemination and another was referred for IVF because of tubal damage seen at the time of the laparoscopic procedure. The third patient had a gradual lengthening of her cycle but is now ovulating regularly in response to tamoxifen. The fourth patient is now responding to gonadotropin therapy, whereas previously she had been unresponsive. Of the two patients who had bilateral diathermy, one ovulated twice and the other four times. Their cycles became longer and both are now ovulating regularly on tamoxifen. One of the patients conceived on tamoxifen, with normal follicular phase LH concentrations, but, unfortunately, miscarried at 6 weeks gestation. Of the four patients who failed to respond after bilateral diathermy, all are now ovulating in response to gonadotropin therapy and three have conceived so far, two after two cycles and one after five cycles. These pregnancies are all ongoing. The overall cumulative conception rate for all patients 6 months after laparoscopic ovarian diathermy was 40%, and the cumulative ongoing pregnancy rate (PR) was.30%. DISCUSSION Bilateral wedge resection of the ovaries was the accepted treatment for polycystic ovaries of the Stein-Leventhal syndrome for over 40 years (6). In a series of 108 patients, Stein (6) reported a pregnancy rate of 85% and stated that the patients "menstruated regularly and remained fertile throughout their normal reproductive span." The efficacy of wedge resection since has been questioned, with lower PRs being reported in other series because of formation of peri-ovarian adhesions in 30% to 100% (7-9). Partial ovarian destruction by laparoscopic diathermy has replaced wedge resection as the surgical therapy for anovulatory women with PCOS. In the first reported series, ovarian diathermy resulted in ovulation in 90% and conception in 70% of the 62 women treated (1). The outcome of 62 pregnancies was no different from the normal population and the miscarriage rate was 15% (10). A number of subsequent studies have produced similarly encouraging results, although the techniques used and degree of damage caused to the ovary vary considerably. Gjonnaess (1) cauterized each ovary at five to eight points, for 5 to 6 seconds at each point with 300 to 400 W. Using the same technique, Dabirashrafi et al. (11) reported mildto-moderate adhesion formation in 20% of patients. Naether et al. (12) treated 5 to 20 points per ovary, with 400 W for approximately 1 second and found that the rate of adhesions was 19.3% and that this was reduced to 16.6% by peritoneal lavage with saline (13). In an earlier study, Naether et al. (14) found that the postdiathermy fall in serum T concentration was proportional to the degree of ovarian damage, with up to 40 cauterization sites being used in some patients. The greater the amount of damage to the surface of the ovary the greater the risk of peri-ovarian adhesion formation. This lead Armar (5), from our group, to develop the strategy of minimizing thl;l number of diathermy points. We have used Armar's technique (5), in which the ovary is cauterized at four points. The high PR (86% of those with no other pelvic abnormality) reported by Armar and Lachelin (2) indicates that the small number of diathermy points used in our method appears to lead to a low rate of significant adhesion formation. In terms of adverse effects the reduction in damage produced by unilateral diathermy can only be of benefit to the patient. In terms of efficacy, however, the results of our small study were disappointing, with only 50% of the patients responding, albeit 75% of the four patients who were treated with unilateral diathermy. All of the patients had been very resistant cases of PCOS, in that they had failed previously to respond to ovulation induction with antiestrogens and gonadotropins. All of the patients developed regular ovulatory cycles after laparoscopic ovarian diathermy and became responsive to adjuvant anti-estrogen or gonadotropin therapy. So far, four patients have conceived. The endocrine changes after ovarian diathermy Vol. 62, No.5, November 1994 Balen and Jacobs Unilaterallaparoscopic ovarian diathermy 923

4 have been explored in detail by a number of groups. Greenblatt and Casper (15) studied six patients and found that serum androgen concentrations fell to a nadir by the 3rd postoperative day and this preceded a fall in serum E 2 and LH concentrations, which then coincided with a rise in serum FSH concentration by day 2 to day 3. It was postulated that ovarian trauma impaired local production of androgens and hence a reduction in extra-ovarian production of estrone, which in turn would decrease positive feedback on LH secretion. Negative feedback on FSH secretion would diminish concurrently, caused by both a decrease in peripheral estrogens and also, possibly, ovarian inhibin (16). Gadir et al. (16) found a significant fall in serum LH and T concentrations and examined LH pulse frequency, which was unaltered after laparoscopic ovarian diathermy. Rossmanith et al. (17) also noted no change in pulse frequency of LH secretion and observed an attenuation in GnRH-stimulated LH after treatment, suggesting an alteration of ovarian-pituitary feedback that affects the sensitivity of the pituitary to GnRH. In two small series ovulation was induced in approximately 70% of patients and the serum T concentrations fell significantly, whereas there was no change in the mean serum LH concentrations (18, 19). Naether et al. (12) observed a decline in serum androgen concentrations and a slight increase in serum gonadotropin levels. Most series, however, report a fall in both androgen and LH concentrations and an increase in FSH concentrations (5, 17, 20). A fall in serum LH concentrations both increases the chance of conception and reduces the risk of miscarriage, as demonstrated by Armar and Lachelin (2), who observed a miscarriage rate of 14% in 58 pregnancies compared with the expected miscarriage rate of 30% to 40% seen in reports of hormonal induction of ovulation in women with PCOS (21). Compared with medical ovulation induction, the additional advantage of laparoscopic diathermy is that it need only be performed once and intensive monitoring is not required because there is no danger of multiple ovulation or ovarian hyperstimulation. Whether patients respond to laparoscopic ovarian diathermy appears to depend on their pretreatment characteristics, with patients with high basal LH concentrations having a better clinical and endocrine response. In Gadir's study (22) it was found that neither the pretreatment T level, body mass index, or ovarian volume could be used to predict outcome. We also found that the only significant difference between the responders and nonresponders was a postdiathermy fall in serum LH concentration, indicating the important role of LH in the anovulatory infertility of these patients (3). The mechanism of ovulation induction by laparoscopic ovarian diathermy is uncertain. It appears that minimal damage to an unresponsive ovary either restores an ovulatory cycle or increases the sensitivity of the ovary to exogenous stimulation. Furthermore, the finding of an attenuated response of LH secretion to stimulation with GnRH (17) suggests an affect on ovarian-pituitary feedback and hence pituitary sensitivity to GnRH. Our study goes one step further by demonstrating that unilateral diathermy leads to bilateral ovarian activity, showing for the first time, that ovarian diathermy achieves its affect by correcting abnormal ovarianpituitary feedback. Our own hypothesis is that the response of the ovary to injury leads to a local cascade of growth factors and those such as insulinlike growth factor I, which interact with FSH (23), result in stimulation of follicular growth and the production of the hormone gonadotropin surge attenuating/inhibitory factor, which leads to a fall in serum LH concentrations (24). Furthermore, minimal ovarian damage only is required to achieve this effect. REFERENCES 1. Gjonnaess H. Polycystic ovary syndrome treated by ovarian electrocautery through the laparoscope. Fertil Steril 1984;41: Armar NA, Lachelin GCL. Laparoscopic ovarian diathermy: an effective treatment for anti-oestrogen resistant anovulatory infertility in women with the polycystic ovary syndrome. Br J Obstet Gynaecol 1993;100: Balen AH, Tan SL, Jacobs HS. Hypersecretion of luteinising hormone. A significant cause of infertility and miscarriage. Br J Obstet Gynaecol 1993;100: Conway GS, Honour JW, Jacobs HS. Heterogeneity of the polycystic ovary syndrome: clinical, endocrine and ultrasound features in 556 patients. Clin Endocrinol 1989; 30: Armar NA, McGarrigle HHG, Honour JW, 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: Stein I. Duration of fertility following ovarian wedge resection. Stein-Leventhal Syndrome. West J Surg Obstet Gyne 1964;78: Weinstein D, Polishuk W. The role of wedge resection of the ovary as a cause of mechanical sterility. Surg Obstet Gynecol 1975;141: Adashi EY, Rock JA, Guzick D, Wenz AC, Jones GS, Jones HW. Fertility following bilateral ovarian wedge resection: 924 Balen and Jacobs Unilaterallaparoscopic ovarian diathermy Fertility and Sterility

5 a critical analysis of 90 consecutive cases of the polycystic ovary syndrome. Fertil Steril 1981;36: Toaff R, Toaff ME, Peyser MR. Infertility following wedge resection of the ovaries. Am J Obstet Gynecol 1976;124: Gjonnaess H. The course and outcome of pregnancy after ovarian electrocautery in women with polycystic ovary syndrome: the influence of body weight. Br J Obstet Gynaecol 1989;96: Dabirashrafi H, Mohamad K, Behjatnia Y, Moghadami-Tabrizi N. Adhesion formation after ovarian electrocauterization on patients with polycystic ovarian syndrome. Fertil Steril1991;55: Naether OGJ, Fischer R, Weise HC, Geiger-Kotzler L, Delfs T, Rudolf K. Laparosocopic electrocoagulation of the ovarian surface in infertile patients with polycystic ovarian disease. Fertil Steril 1993;60: Naether OGJ, Fischer R. Adhesion formation after laparosocopic electrocoagulation of the surface in polycystic ovary patients. Fertil Steril 1993;60: Naether 0, Weise HC, Fischer R. Treatment with electrocautery in sterility patients with polycystic ovarian disease. Geburtsh Frauenheilk 1991;51: Greenblatt E, Casper RF. Endocrine changes after laparoscopic ovarian cautery in polycystic ovarian syndrome. Am J Obstet Gynecol 1987;156: Gadir AA, 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 Endocrino\1990;32: Rossmanith WG, Keckstein J, Spatzier K, Lauritzen C. The impact of ovarian laser surgery on the gonadotropin secretion in women with polycystic ovarian disease. Clin Endocrinol 1991;34: Vander Weiden RMF, Alberda AT, de Jong FH, Brandenburg H. Endocrine effects of laparoscopic ovarian electrocautery in patients with polycystic ovarian disease, resistant to clomiphene citrate. Europ J Obstet Gynecol Reprod Bioi 1989;32: Kovacs G, Buckler H, Bangah M, Outch K, Burger H, Healy D, et al. Treatment of anovulation due to polycystic ovarian syndrome by laparoscopic ovrian electrocautery. Br J Obstet Gynaecol 1991;98: Tasaka K, Sakata M, Kurachi H, Komura H, Miyake A, Tanizawa 0. Electrocautery in polycystic ovary syndrome. Horm Res 1990;33:(Suppl 2) Homburg R, Armar NA, Eshel A, Adams J, Jacobs HS. Influence of serum luteinising hormone concentrations on ovulation, conception and early pregnancy loss in polycystic ovary syndrome. Br Med J 1988;297: Gadir AA, Khatim MS, Alnaser HMI, Mowafi RS, Shaw RW. Ovarian electrocautery: responders versus non-responders. Gynecol Endocrinol 1993;7: Adashi EY, Resnick CE, Hernandez ER. Insulin-like growth factor 1 as an amplifier of FSH: studies on mechanism(s) and site(s) of action in cultured rat granulosa cells. Endocrinol 1988;122: Balen AH, Jacobs HS. Gonadotrophin surge attenuating factor: a missing link in the control of LH secretion? Clin Endocrinol 1991;35: Vol. 62, No.5, November 1994 Balen and Jacobs Unilaterallaparoscopic ovarian diathermy 925

Key words: laparoscopic ovarian multiple punch resection, laparoscopic ovarian electrocautery, infertility,

Key words: laparoscopic ovarian multiple punch resection, laparoscopic ovarian electrocautery, infertility, polycystic ovarian syndrome, clomiphene citrate 1) Insler V, Zakut H, Serr M. Cycle pattern