Polycystic ovarian syndrome treated by ovarian electrocautery through the laparoscope

WI I Vol. 41, No.1, January 1984 Printed in U.SA.

FERTILITY AND STERILITY Copyright © 1984 The American Fertility Society

Polycystic ovarian syndrome treated by ovarian electrocautery through the laparoscope

Halvard Gjonnaess, M.D. * Department of Obstetrics and Gynecology, Aker Hospital, Oslo, Norway

Sixty-two women with the polycystic ovarian syndrome were treated by systematic electrocautery of the ovarian capsule performed by laparoscopy. Ovulation occurred within 3 months in 92%. Regular menstrual cycles were established in 51 patients (86%) and plasma progesterone levels suggested that these were ovulatory. Seven of nine women who had been resistant to treatment with clomiphene, 150 mg daily, and human chorionic gonadotropin, 6000 to 9000 IU, ovulated after electrocauterization. The remaining two women responded to stimulation with clomiphene. Pregnancy occurred in 24 of 35 subjects who were involuntarily infertile (69%), with the pregnancy rate increasing to 80% with the inclusion of the women sensitive to clomiphene. These findings support the theory that ovulation is triggered by local factors within the ovary itself Fertil Steril41:20, 1984

Because the polycystic ovarian syndrome (PCO) described by Stein and Leventhal! is not well defined, the comparison of different treatment modalities is difficult. The diagnosis ofPCO is based on a history of irregular anovulatory bleeding; physical signs of obesity, male hair distribution, and acne; the appearance of the ovaries; and the endocrine profile. Many, but not all, will respond to hormone stimulation therapy with either clomiphene citrate (CC) alone or CC and human chorionic gonadotropin (hCG). In some cases, one must resort to wedge resection of the ovaries,! even at the risk of producing pelvic adhesions in up to 25% of cases, and thus converting the infertility from one with an endocrine cause to one with a mechanical cause. 2 -4 Some clinics still use wedge resection as

Received June 22, 1983; revised and accepted September 6, 1983. *Reprint requests: Halvard Gjonnaess, M.D., Department of Obstetrics and Gynecology, Aker Hospital, Oslo 5, Norway. 20

Gjonnaess Ovarian electrocautery in peo

the routine treatment for infertility in women with PCO. 5 With a microsurgical technique, the postoperative pelvic adhesions can presumably be reduced. To eliminate adhesions and minimize the operative trauma of wedge resection, we have developed a method based on systematic electrocautery of the ovarian capsule performed through a laparoscope. The purpose of this article is to describe this technique and to demonstrate its effects on the ovarian function and infertility caused by PCO. The endocrine effects of ovarian electrocautery, other than ovulation, are the subject of another article. MATERIALS AND METHODS

Between the years 1978 and 1982, 65 women with PCO were treated at the gynecology department of Aker Hospital. Three of them were lost to follow-up. The criteria for inclusion in the study were menstrual irregularities; an endocrine profile showing progesterone (P) values with no luFertility and Sterility

Table 1. Duration of Irregularitya Age

1--3 years

> 3 years

Always

yr

n

n

n

0 4 0

1 6 5

3 34 4

< 20 20-30 > 30

"The information is lacking in some cases.

teal phase, serum concentrations of luteinizing hormone (LH) and androgenic hormones in the upper "physiologic range" or increased, and low sex-hormone-binding globulin; and the appearance of the ovaries with a smooth, white, thickened capsule, often with small cysts. In this series, 3 women were less than 20 years old, 48 were between 20 arid 30, and 11 were more than 30 years old. The distribution of the age at menarche was similar to that seen in the population at large 6 : 50 cases, 11 to 15 years; 11, 15 to 18 years; and 1, 18 years. About two thirds had experienced irregular menstrual bleeding from the onset of menarche (Table 1). Once the pattern of irregularity was established, only ten women had ever recorded a menstrual cycle of 4 weeks (Table 2). Almost all the patients had prolonged cycles. Some had had amenorrhea for "several years," and 25 had had amenorrhea for at least the last 6 months preceding electrocautery. Forty-eight women presented with involuntary infertility, and 14 were examined for other reasons (Table 3). Fourteen women had been previously pregnant (8 living infants and 6 abortions), 4 of them 3 to 4 years earlier, and 10 more than 5 years before. Obesity was recorded in 25 cases, hirsutism in 42, and acne in 28. These characteristics were judged subjectively and not standardized objectively. An ordinary angled Wolf laparoscope (Richard Wolf GmbH, Knittlingen, West Germany) was introduced into the peritoneal cavity through the umbilicus. A unipolar biopsy or sterilization forceps was held against the ovarian surface. As we emphasize in all work using unipolar cautery, the ovaries were fixed in such a position that damage to other pelvic organs was minimized. The current was the same as that used in the sterilization procedure. A Siemens Radiotom 619B (Siemens AG, Erlangen, West Germany), with a frequency of 1.75 MHz generating between 200 and 300 watts was used. The electrode was pressed against the ovarian surface for 2 to 4 seconds, Vol. 41, No.1, January 1984

sufficient to penetrate the ovarian capsule. During the course of the study, the number of points cauterized (holes made in the capsule) was increased from three to four to five to eight in each ovary. At the end of the procedure, the ovaries appeared as seen in Figure 1, with the diameter of each hole ~ 3 mm and the depth 2 to 4 mm. The endocrine profile was determined by the standard methods used at the hormone laboratory, Aker Hospital. Hormones measured were LH, follicle-stimulating hormone, prolactin, sexhormone-binding globulin, testosterone, dihydrotestosterone, androstenedione, dihydroepiandrosterone sulfate, P, 17-hydroxyprogesterone, estradiol, cortisol, and 11-deoxycortisol. Serum P values of 25 nmol/l or more were taken as evidence of ovulation; 9 to 25 nmolll were borderline levels, suggesting that ovulation had probably taken place, but that the time chosen for blood sampling was suboptimal.

RESULTS OVULATION

More than 90% of subjects ovulated within 3 months of electrocautery (Table 4). Of the 42 women who established regular 4-week cycles, plasma P values of> 25 nmolll were measured in 35, and borderline levels were measured in 7. Seven of nine patients with prolonged but regular intervals of 4 to 6 weeks had ovulatory values, and the remaining two had borderline values. Thus, ovulation probably occurred in all 51 women who established a regular menstrual pattern. Five women had noticed some change in the rhythm, but no regularity, and three had noticed no change at all. Three of these cases had serum P levels of 33.8, 14.4, and 12.0 nmolll, indicating that in those women who did not establish a regular cycle after electrocautery, ovulation had only occurred in 37.5% (3 of 8). The effect of electrocautery did not depend on ovarian size: ovulation was induced in 5 of 6 Table 2. Length of Intervals Observed Weeks

4 4-6 6-12 > 12

Shortest

Longest

n

n

0 3

10 14 23

11

11

46

Gj6nnaess Ovarian electrocautery in peo

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Table 3. Involuntary Infertility in Women with PCO n

Involuntary infertility solely because of PCO

n

%

Pregnancy or plasma P > 25 nmoUI Plasma P 9-25 nmoUI

46

74

11

18

Ovulation revealed in

57/62

92

62

Total series Voluntary infertility Tubal factors Subfertile husbands

Table 4. Ovulation After Ovarian Electrocautery in 62 Women withPCO

14 9

4

27 35

women with normal-sized ovaries (83%), 35 of 36 women with ovaries from 4 to 6 cm (97%), and 17 of 20 women with ovaries exceeding 6 cm (85%). However, the number of points cauterized was probably important, because the best results were seen in those cases where there were ten or more points in the two ovaries together (Table 5). Nineteen women had received CC therapy previously, with consequent ovulation in 6 cases. Four other patients ovulated after treatment with CC, 150 mg daily for 5 days, followed by hCG, 6000 to 9000 IV; but nine were refractory to this treatment. In addition, two of them developed hypersensitivity reactions to the hCG injections. Following electrocautery, 17 of these 19 patients ovulated. The two nonresponders, who had also been resistant to CC and hCG, had only minor changes in their bleeding patterns. However, after electrocautery, they both responded to additional CC treatment, one ovulating after 50 mg

daily for 5 days and the other requiring 150 mg daily for 5 days. Several years prior to electrocautery, four patients had undergone wedge resection, resulting in a transient improvement in the menstrual rhythm in three. All four ovulated after cauterization. MENSTRUATION

There were no great differences in the timing of the onset of the first menses after cautery. Fifty occurred within 4 to 6 weeks, with a mean of 31.4 days (standard deviation, 6.7 days). Vaginal bleeding occurring the first few days after therapy was discounted, because it could well have been a result of the intrauterine instrumentation during laparoscopy. Excluding the 3 women who became pregnant within 7 weeks, 51 of 59 patients established regular menstrual cycles after electrocautery (86.4%). Twelve of the 32 women who did not become pregnant within the observation period were observed for more than 2 years. The treatment effects of electrocautery on the cycles lasted for more than 2 years in three women, 1 to 2 years in six, and for less than 1 year in the remaining three (Table 6). Thus, the effects of electrocautery on the ovaries are probably of limited duration. PREGNANCY

Of the 62 patients with PCO, only 35 were infertile because of PCO alone (Table 3). TwentyTable 5. Ovulation After Ovarian Electrocautery Related to the Number of Points Electrocauterized Ovulation induced Points

Total series

n

%

4 24 29

66.7 92.3 96.7

n

Figure 1 The ovary after electrocautery for the treatment of peo. 22

l_

Gjonnaess Ovarian electrocautery in PCO

<6 6-10 > 10

6

26 30

Fertility and Sterility

j

Table 6. Duration of the Effect of Electrocautery Observation time yr

Menstrual cycle remained regular for < 1 year

1-2 years

> 2 years

Pregnant

Unknown

Total

n

n

n

n

n

n

1 3

16 16 14 16

4

62

<1 1-2 2-3 >3

9 2 2 1

9 3 3

2 1

6 5 7 8

Total

14

15

3

26a

aIncludes the two patients with pelvic adhesions and a subfertile husband, respectively.

four of them became pregnant with no other treatment than electrocautery (69%). The majority of pregnancies occurred within the first year of therapy (Table 7). Four patients became pregnant after additional CC therapy: patient 1 had previously been resistant to CC, and she had relatively few points cauterized (three to five in each ovary). There was no change in her bleeding pattern, and spontaneous ovulation could not be shown. After electrocautery, however, she responded to CC treatment. Patient 2 also had relatively few points treated, and even though she ovulated several times, the effect lasted for only 6 months. CC treatment resulted in pregnancy. Patients 3 and 4 each had two to three points treated in each ovary (they were from the early part of the series). They both had borderline P values and were given CC within 1 year, partly because of impatience. Of the involuntarily infertile women, five had borderline levels of P. In addition to patients 3 and 4 cited above, another two patients became pregnant without further therapy, demonstrating that ovulation had occurred. Including patient 1, who became sensitive to CC after cauterization, 25 of the 35 women with PCO as the sole cause of their infertility owed their pregnancies to the electrocautery of the ovaries (71.4%). In toto, 28 of 35 patients became pregnant (80%). Pregnancy also occurred in one woman who had pelvic adhesions treated at the same time and in another woman with a subfertile husband, but these are not included in the statistics. During the observation time, four women had two pregnancies each; two had not responded to the combination of CC and hCG previously. Pelvic adhesions following electrocautery were not looked for systematically. In five patients who subsequently underwent cesarean section, there were no adhesions present; but in one woman who Vol. 41, No.1, January 1984

did not conceive and who revealed a thick, prominent, and fibrous keloid after laparoscopy, fibrous periovarian adhesions were found 3 years later. OTHER EFFECTS

The physical signs of PCO-acne, obesity, and male hair distribution-are hard to evaluate, and there may be factors other than PCO responsible. Changes in the acne and hair distribution might, however, be indicative of a change in the endocrine profile. Of interest, 28 patients with acne claimed an improvement in their skin problems. Except for the usual side effects associated with a general anesthetic and laparoscopy, no untoward side effects from the ovarian electrocautery were noted. DISCUSSION

The natural course of the disease is unpredictable in the PCO syndrome. Ovulation and pregnancy may occur spontaneously even after prolonged periods of amenorrhea. Despite this, it seems reasonable to accept the occurrence of ovulation within 3 months of ovarian electrocautery in 92% of patients as an effect of therapy, even in the absence of a controlled study. This result must be compared with the reported 52% to 86% Table 7. Interval Between Ovarian Electrocautery and Pregnancy . Interval < 1 rno 1-3 rno 3-6rno 6--12 rno 12-18 rno 18--24 rno > 2yr Pregnant after ovarian electrocautery solely

n 2 4 6 6 2 3 1

24

Gj6nnaess Ovarian electrocautery in peo

23

,

. . ~~.--------------~--------------~

I ovulation rates obtained by wedge resection l -5, 7 and the 67% to 76% rates after CC treatment.8-l0 Pregnancy occurred in 69% of patients (80% when patients receiving additional CC were included) after ovarian cauterization. Following wedge resection, the pregnancy rates vary widely from 25% to 71%,2,3,5,7, 11 and with CC, from 30% to 61%.8-10, 12 Using laparoscopic electrocautery, there are a number of advantages in addition to the favorable pregnancy outcome. Laparoscopy is in itselfa diagnostic tool, to exclude other causes of infertility and, if necessary, deal with them if present, at the same time sparing the patient for a laparotomy or repeated ovulation induction. One would assume that this technique would cause fewer pelvic adhesions thana wedge resection, because there are no bleeding points. Electrocautery of the ovaries is equally effective in patients who have been resistant to ovulation induction. In some cases; although apparently inadequate alone, the cauterization seems to render the ovaries more responsive to CC. A recent article1;j has described the celioscopic resection of small ovarian fragments. However, the results of this technique in 12 patients with PCO were not as favorable as those of electrocautery: ovulation was induced in only 45%, and pregnancy was achieved in 42%. The triggering mechanism for ovulation seems to be located in the ovaries in these cases, because cauterization of the ovarian capsule was the only treatment given. There appears to be a correlationbetween the number of points cauterized and the ovulation rate. Whether ovulation is elicited by nonspecific ovarian stromal destruction, extensive capsular destruction with discharge of the contents of a number of subcapsular follicle cysts, or the local capsular cautery of one specific but unidentified follicle cannot be ascertained from this study. Preliminary studies indicate that the tissue damage caused by the cautery is superficial and limited to the capsule and a few millimeters of the underlying tissue. In their original paper, Stein and Leventhal l suggested that the effect of the wedge resection was due to the removal of the cortex containing the cysts. This hypothesis agrees with our observations, but they do not discuss the underlying mechanism. Goodman et al. 14 and, more recently, Hodgen 15 have studied these mechanisms. They experimented with electrocauterization ofthe ripening follicles in monkeys and concluded that the

ovulation mechanism is regulated by the ovary itself, by the selection of a "dominant follicle," which then inhibits the maturation of the other follicles. The theory is corroborated by experiments on rats. 16 Following cautery of this "dominant follicle," the LH surge appeared after a delay corresponding to the duration of a normal follicular phase, with menses appearing in due time. Our patients also had their first menses after therapy within a reasonable "normal" human intermenstrual interval. Thus, our findings support the theory that to some extent, ovulation is regulated from the ovary itself, probably by an inhibiting principle ("dominant follicle," "inhibin"), which is destroyed by electrocautery of the ovarian capsule, thus allowing ovulation to occur.

REFERENCES 1. Stein IF, Leventhal ML: Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29:181, 1935 2. Weinstein D, Polishuk WC: The role of wedge resection of the ovary as a cause for mechanical sterility. Surg Gynecol Obstet 141:417, 1975 3. Starup J: Treatment of patients with polycystic disease of the ovary. II. Ugeskr Laeger 138:2866; 1976 4. ToaffR, ToaffME, Peyser MR: Infertility following wedge resection of the ovaries. Am J Obstet Gynecol 124:92, 1976 5. Lunde 0: Polycystic ovarian syndrome: a retrospective study of the therapeutic effect of ovarian wedge resection after unsuccessful treatment with clomiphene citrate. Ann Chir Gynaecol 71:330, 1982 6. Brundtland GH, Walll!le L: Menarchal age in Norway: halt in the trend towards earlier maturation. Nature 241:478, 1973 7. Thodes P: The effects of wedge resection of the ovaries in 63 cases of the Stein-Leventhal syndrome. J Obstet Gynaecol Br Commonw 75:1108, 1968 8. MacGregor AH, Johnson JE, Bunde CA: Further clinical experience with clomiphene citrate. Fertil Steril 19:616, 1968 9. Rust LA, IsraelR, Mishell DR: An individualized.graduated therapeutic regime for clomiphene citrate. Am J Obstet Gynecol 120:785, 1974 10. Raj SG, Thompson IE, Berger MJ, Taymor ML: Clinical aspects of the polycystic ovary syndrome. Obstet Gynecol 49:552, 1977 11. Vejlsted H, Albrechtsen R: Biochemical and clinical effect of ovarian wedge resection in the polycystic ovary syndrome. Obstet Gynecol 47:575, 1976 12. Fayez JA: Selection of patients for clomiphene citrate therapy. Obstet Gynecol 47:671, 1976 13. Campo S, Garcea N, Caruso A, Siccardi P: Effect of celioscopic ovarian resection in patients with polycystic ovaries. Gynecol Obstet Invest 15:213, 1983

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14, Goodman AL, Nixon WE, Johnson DK, Hodgen GD: Regulation of folliculogenesis in the cycling rliesus monkey: selection of the dominant follicle. Endocrinology 100:155, 1977 15. Hodgen GD: The dominant ovarian follicle. Fertil Steril 38:281, 1982

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16. Phillips A, Hahn DW, Channing .CP: The effect ofp.orcine follicular flUid on ovulation: mating and pregnancy in the rat. ContrllCeption 26:617; 1982

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