Surgical ovulation induction: The role of ovarian diathermy in polycystic ovary syndrome

7 Surgical ovulation induction: the role of ovarian diathermy in polycystic ovary syndrome B A R R Y W. D O N E S K Y ELI Y. A D A S H I The symptoms attributable to chronic anovulation are the main reasons that women with polycystic ovary syndrome (PCOS) present themselves to clinicians. Not surprisingly, a major complaint is the infertility that accompanies PCOS. Prior to the introduction of ovulation-inducing medical agents, such as clomiphene citrate or human menopausal gonadotrophins (hMG), ovarian surgery was the only known treatment for this condition. First introduced by Stein and Leventhal in 1935 (Stein and Leventhal, 1935), laparotomy with bilateral ovarian wedge resection (BOWR) rapidly gained popularity as an increasing number of reports cited positive anecdotal experience. From 1935 until the early 1980s, numerous uncontrolled case series were published in the literature and documented pregnancy rates ranging from 25% to as high as 86.7% (Donesky and Adashi, 1995). During the 1970s and early 1980s, several investigators noted a high incidence of post-operative adhesive disease following BOWR (Stein, 1966; Kistner, 1969; Buttram and Vaquero, 1975; Toaff et al, 1976; Adashi et al, 1981). These adhesions were deemed responsible for the suboptimal pregnancy rates reported by many of the published case series. In the light of the medical ovulation induction agents that had by then become available, a consensus formed to the effect that BOWR should play a minimal role in the treatment of PCOS. Today, BOWR is all but obsolete, having been replaced by medical agents. The anti-oestrogenic compounds (primarily clomiphene citrate) are the most common medications currently used for ovulation induction in the PCOS setting. While the importance of the development of clomiphene citrate can hardly be overstated, several problems are associated with its use. While 70-80% of PCOS patients will achieve ovulatory cycles in response to clomiphene citrate, only about 50% will conceive. In addition, some reports have noted high rates of spontaneous miscarriage following the use of clomiphene citrate (Garcia et al, 1977; Nunley et al, 1985). Last, a small but significant increase in the rate of multiple gestation occurs with the use of clomiphene citrate. BailliOre's Clinical Endocrinology a n d Metabolism - 293 Vol. 10, No. 2, April 1996 ISBN 0-7020-2100-8 0 9 5 0 - 3 5 1 ) ( / 9 6 / 0 2 0 2 9 3 + 17 $12.00/00

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In patients resistant to clomiphene citrate, gonadotrophin therapy has traditionally been the next step. While able to induce ovulation in most subjects, gonadotrophins are fraught with many of the same disadvantages of clomiphene citrate, including increased rates of multiple gestation and rates of spontaneous abortion, which are higher than those for conceptions occurring without ovulation induction therapy (Wang and Gemzell, 1980). Additionally, the risk of ovarian hyperstimulation syndrome increases significantly with these medications, which necessitates careful monitoring during their administration. The above concerns, coupled with the development of operative laparoscopy, have renewed interest in the surgical approach to ovulation induction, particularly for those patients who, in spite of rigorous attempts at clomiphene citrate ovulation induction, remain anovulatory. Advocates of laparoscopy claim a lower risk of post-operative adhesion formation compared with laparotomy (Portuondo et al, 1984; Luciano et al, 1989; Luciano, 1990). Other arguments in favour of the laparoscopic approach include the minimal morbidity associated with a laparoscopic procedure and the fact that virtually no cyclic monitoring of ovulation induction is required, as one treatment may, in principle, produce many ovulatory cycles. In addition, there appears to be no increased risk of multiple gestation or ovarian hyperstimulation with these procedures, and some series have even suggested that the spontaneous miscarriage rate is lower compared with that encountered following the medical induction of ovulation (Abdel Gadir et al, 1990b, 1992). Several methods of laparoscopic treatment have been studied, including electrocautery (also known as diathermy), laser 'drilling' and multiple biopsy. The specifics of these methods are described in detail elsewhere (Donesky and Adashi, t995). Each of these methods shares the common goal of creating focal areas of damage to the ovarian cortex and/or stroma. There is no evidence to suggest that one method consistently produces clinical results superior to another, so for all practical purposes they can all be viewed as equivalent procedures. The most extensively studied method has been electrocautery. O U T C O M E ANALYSIS

Pregnancy rates An adequately randomized controlled study comparing the efficacy of laparoscopic treatments with those of established medical therapies has yet to be performed. While a number of case series exist, most suffer from deficiencies in the documentation of the diagnosis of PCOS, in the definition of follow-up intervals, in the sporadic documentation of postoperative ovulation and in the lack of correction for other infertility factors. Our most recent count shows there are 35 reports in the English language literature (Table 1). Of these, two articles (Gj6nnaess, 1994; Naether et al, 1994) appear to be extensions of earlier reports (Gj6nnaess, 1984, 1990;

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Naether et al, 1993). Where more than one paper concerns the same patients, only the most recent report has been included in our totals. One report (Cohen, 1979) was based on information obtained through unpublished personal communications and we elected not to include it in our totals. As shown in Table 1, results from total of 947 patients were available for analysis. Following the procedure, 561 became pregnant one or more times (59.2%, range 20-88%), and 778 (82.1%) ovulated either spontaneously or with the addition of medications (predominantly clomiphene citrate) to which they had not responded pre-operatively. If those subjects who did not resume ovulation post-operatively are excluded from the denominator, 561 of 778 ovulatory patients conceived (72.1%). These conception rates compare favourably with those reported for PCOS subjects who undergo ovulation induction with hMG or 'pure' follicle-stimulating hormone (FSH). Table 1. Summary of conceptions following laparoscopic ovulation induction. Author

Year

N

Campo et al Aakvaag and Gjonnaess Greenblatt and Casper van der Weiden and Alberda Sumioki et al Daniell and Miller Yanagibori et al Kojima et al Armaretal Abdel Gadir et al Keckstein et al Sakata et al Tasaka et al Utsunomiya et al Giirgen et al Kovacs et al Rossmanith et al Gfirgen et al Ostrzenski Armar and Lachelin Campo et al Verhelst et al Tiitinen et al Greenblatt and Casper Szil~igyi et al Balen and Jacobs Gj6nnaess Naether et al

1983 1985 1987 1987 1988 1989 1989 1989 1990 1990b 1990 1990 1990 1990 1991 1991 1991 1992 1992 1993 1993 1993 1993 1993 1993 1994 1994 1994

12 58 6 11 7 85 6 12 21 29 27 9 i1 16 17 10 11 40 t2 50 23 17 10 8 4 10 219 206

Total

947

Method

Ovulation* (%)

Biopsy [69% (cycles)] Unipolar 53 (91) Unipolar 5 (83) Unipolar 9 (82) Biopsy 6 (86) COJKTP 60 (71) Nd/YAG [NA] Nd:YAG 10 (83) Unipolar 17 (81) Unipolar 25 (87) Nd:YAG 19 (70) Unipolar 8 (89) Unipolar 10 (91) Biopsy 15 (94) Unipolar/Nd:YAG 12 (71) Unipolar 9 (90) Nd:YAG 8 (72) Nd:YAG 28 (70) CO 2 12 (100) Unipolar 45 (92) Biopsy 14 (61) CO2 14 (82) Unipolar 7 (70) Unipolar 8 (100) Nd:YAG 3 (75) Unipolar 10 (100) Unipolar 201 (92) Unipolar [77% (cycles)] 778 (82.1)

Pregnancyt (%) 5 (42) 24 (42) 4 (67) 5 (45) 4 (57) 48 (56) 3 (50) 7 (58) 11 (52) 14 (48) 10 (37) 3 (33) 4 (36) 8 (50) 8 (47) 4 (40) 4 (36) 20 (50) 9 (75) 31 (62) 13 (56) 11 (65) 2 (20) 7 (88) 1 (25) 4 (40) 152 (69) 145 (70) 561 (59.2)

* Includes spontaneous ovulation and ovulation occurring post-operatively with medical agents to which the subjects were previously unresponsive. t- Number and percentage of patients achieving pregnancy at least once. Adapted from Donesky and Adashi (1995, Fertility and Sterility 63: 439-463) with permission.

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One addtional study (Fukaya et al, 1995) used laser vaporization of the ovarian surface in 26 subjects with PCOS who had previously developed ovarian hyperstimulation during gonadotrophin therapy. Following the procedure, 9 patients (34.6%) ovulated either spontaneously or with clomiphene citrate. In the remaining 17 subjects, there was a substantial reduction in the incidence and severity of ovarian hyperstimulation with subsequent gonadotrophin cycles. Overall, 19 out of 26 patients (73%) conceived, with only 3 (15.8%) multiple gestations (all twins) occurring. Post-operative endocrine alterations

The effects of laparoscopic methods of ovulation induction on several important reproductive hormones have been studied (Table 2). When measured, a fall in oestradiol is generally noted in the few hours following the procedure. Most agree that while luteinizing hormone (LH) levels are transiently increased during the 24-48 hours immediately following surgery, a fall in both immunoreactive LH levels and LH bioactivity occurs thereafter (Sumioki et al, 1988). Several authors (but not all) have also noted a post-operative increase in the circulating levels of FSH; however, most studies agree that the LH/FSH ratio decreases. Testosterone and androstenedione levels were noted to fall post-operatively in nearly all studies. The fall in androstenedione, however, appears to be somewhat transitory, but the fall in testosterone appears to be more long-lasting. Temporary decreases in inhibin concentrations have also been reported, but they appear to return to base-line within a week or so post-operatively (Kovacs et al, 1991). Central opioid and dopaminergic control over gonadotrophin secretion appears to remain unaffected by ovarian smgery (Szilfigyi et al, 1993). Effects on intra-abdominal adhesion formation and ovarian atrophy

The interest in laparoscopic alternatives to BOWR is, in large part, due to the concept that laparoscopy--characterized by the lack of tissue-dying effects and the absence of direct tissue handling--should result in less adhesion formation compared with laparotomy (Luciano et al, 1989; Luciano, 1990). Nevertheless, increasing surgical experience has shown that the mere avoidance of laparotomy does not ensure an adhesion-free outcome (Operative Laparoscopy Study Group, 1991). The earliest reports on laparoscopic methods of ovulation induction either noted no adhesions in women undergoing caesarean section following such treatment for PCOS (Daniell and Miller, 1989; Armar et al, 1990) or observed translucent adhesions judged of limited consequence to the normal tubo-ovarian relationship (Gj6nnaess, 1984). Such studies, however, represent a clear selection bias in favour of a normal pelvis by virtue of the fact that they were performed only when a pregnancyhad occurred. In the absence of systematic evaluation of all patients (especially those who did not conceive), no valid conclusions can be made on the incidence of post-operative adhesion formation. In those instances in which follow-up

1983 1985 1987 1987 1988 1989 1990 1990a 1990 1990 1990 1990 1991 1991 1992 1993 1993 1993 1993 1993 1995

Campo et al Aakvaag and Gj6nnaess Greenblatt and Casper GjOnnaess and Norman Sumioki et al Kojima et al At-mar et al Abdel Gadir et al Keckstein et al Sakata et al Tasaka et al Utsunomiya et al Kovacs et al Rossmanith et al Ostrzenski Abdel Gadir et al Naether et al Campo et al Verhelst et al Tiitinen et al Fukaya et al

N 12 58 6 16 7 12 21 20 30 9 11 16 10 11 12 29 33 23 17 10 26

NS 1" I" 1" -[NS Variable 3, ,[. 1" 3, NS NS -1. 1" ,1, 1" NS NS .1, -

~< 24 hours NS $ $ 3` $ NS $ 3, ,1. ,[. $ NS NS 3` .], NS NS NS ,], 3,

~> 48 hours

~ 3, NS NS I" $ ,1, -], 3, ,1,

NS $ $ .1. 3, NS 1"

Androstenedione

NS = no significant changes observed; 1' = Significant increase observed: $= Significant decrease observed; - = item not studied. Adapted from Donesky and Adashi (1995. Fertility and Sterility 63: 439-463) with permission.

Year

Author

LH

Table 2. Hormonal patterns observed after laparoscopic ovulation induction.

~ NS 1" NS NS NS

1" 1" NS NS NS 1" $ ,t, NS NS 3,

FSH

NS $ ,l,[$ -]. ,1. 3, ,1. ,[. -]. ,l, $ ,], -1. $ ,[, ,l, 1"

Testosterone

1",3 --,,,I

('3 ©

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laparoscopy was performed on women failing to conceive post-operatively, a high incidence of generally mild adhesion formation was documented (van der Weiden and Alberda, 1987). Keckstein, in turn, reported post-operative adhesions in 3 out of 7 patients treated with a carbon dioxide laser and in none out of 4 treated with the Nd:YAG laser (Keckstein et al, 1990). Kovacs noted the absence of adhesions in a single patient (Kovacset al, 1991). Dabirashrafi presented selective data on 8 out of 17 subjects who underwent laparoscopic ovarian electrocautery and who subsequently underwent a second operation. No adhesions were noted. In a second unselected group, he performed a second-look laparoscopy on each of 14 patients following laparoscopic electrocautery or biopsy. In this manner, he identified four patients with adnexal adhesions (Dabirashrafi et al, 1991). Gtirgan et al followed 17 patients who underwent laparoscopic treatment coupled with a second-look laparoscopy 3 4 weeks after initial surgery. Of 7 patients in whom cautery had been used, only 1 was adhesion-free. The other 6 all had some degree of adhesion formation (2 minimal, 3 mild and 1 moderate). Following use of the Nd:YAG laser (extolled in other reports for its good coagulation effects, and thus no bleeding and hopefully less tendency to promote adhesions), 8 out of 10 patients displayed adhesions (4 minimal, 3 mild and 1 moderate). Thus, out of 17 patients, 14 (82%) had adhesive disease present (Gtirgan et al, 1991). Greenblatt and Casper reported on 8 patients treated with laparoscopic electrocautery. All 8 patients had pelvic adhesions present. Where interceed barrier (oxidized regenerated cellulose) was used, it was ineffective in preventing adhesion formation (Greenblatt and Casper, 1993). In summary, the data available reveal that adhesion formation, far from being a rare occurrence following laparoscopic treatment, is the rule rather than the exception. On the other hand, the significance of minimal adhesions to fertility is still unknown. Gtirgan et al, in a second report, performed a prospective randomized controlled study in which pregnancy rates were compared between 19 patients who underwent second-look laparoscopy and lysis of adhesions when present (13 out of 19) and 20 patients who did not undergo second-look laparoscopy. No significant difference in pregnancy rates was observed (Gtirgan et al, 1992). Likewise, they noted that while all 8 patients in her series had adhesions, 7 out of 8 (87.5%) conceived following the procedure (Greenblatt and Casper, 1993). Thus, although a high rate of adhesion formation is undeniable, these small studies suggest that lysis of the adhesions may not improve subsequent pregnancy rates (or perhaps that the adhesions are not of sufficient severity to prevent conception). In addition to adhesion formation, a case of unilateral ovarian 'atrophy' has been reported following the procedure (Dabirashrafi, 1989) and speculative, but nonetheless concerning, questions regarding the potential for inducing epithelial ovarian cancers have been raised. In summary, while preliminary data as to the safety of these procedures appear encouraging, conclusions drawn for clinical practice must be made with caution. The large-scale studies needed to settle the issues have yet to be performed.

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Miscarriage Current evidence suggests that (for reasons that are not entirely clear) the rate of spontaneous miscarriage in women with PCOS is elevated compared with that in women without PCOS. Sagle et al (1988) noted a disproportionately high prevalence of PCOS in a group of women who had experienced recurrent abortion (82%), compared with a control group of parous women (18%). The most convincing reasons given for the increased rate of early pregnancy loss in PCOS relate to the elevated circulating levels of LH observed in many of these women. Interestingly, PCOS subjects who do not have elevated levels of LH appear to have no increase in miscarriage rates above those found in the normal population (Homburg et al, 1988). In contrast, numerous studies in the literature have noted an adverse effect of elevated LH levels on fertility (Stanger and Yovich, 1985; Regan et al, 1990; Homburg et al, 1993; Shoham et al, 1993). While elevated LH levels are often accompanied by elevated levels of circulating androgens, there does not appear to be an increase in miscarriage rates unless LH is also elevated (Conway et al, 1989). This fact, combined with the data mentioned above, makes a compelling case for elevated LH levels being the common denominator associated with and possibly causally related to the subfertility seen in PCOS. Recent reviews by Shoham et al (1993) and Balen et al (1993) discuss possible mechanisms by which hypersecretion of LH might impair oocyte quality. Briefly, the excess LH may allow the premature resumption of meiosis. The oocyte would then be prematurely 'aged' upon ovulation or retrieval. Such post-mature oocytes have been observed during in vitro fertilization (irrespective of PCOS) and were noted to have lower rates of fertilization, cleavage and implantation. Further adverse effects of elevated LH levels on the oocyte might be mediated via changes in the antral steroidogenic environment, leading to premature progesterone production. In the mouse, at least, oocytes prematurely exposed to progesterone undergo meiotic arrest and atresia more readily than do controls (Tyler et al, 1980). The above theories also help to explain why suppression of follicular phase LH levels seems to decrease early pregnancy loss. What remains to be seen, however, is whether a medical or a surgical approach will prove to be the better method for treating the problem. So far, only one prospective study attempts to address the issue. Abdel Gadir et al carried out a prospective trial in which PCOS subjects were randomized to receive ovulation induction with gonadotrophins following either downregulation with a gonadotrophin-releasing hormone (GnRH) agonist (N = 17) or laparoscopic ovarian electrocautery (N= 16) (Abdel Gadir et al, 1992). No differences were noted in pregnancy rates or in the rate of ovulation between the two groups. However, the authors noted that the group receiving electrocautery displayed fewer cycles with multiple dominant follicles, consistently lower luteal phase serum testosterone levels and a lower rate of early pregnancy loss: 1 out of 7 patients (14%) in the electrocautery group versus 4 out of 8 patients (50%) in the GnRH agonist-hMG group. Some caution must be

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exercised when interpreting this study, however, as the number of patients was too small for the differences in miscarriage rate to reach statistical significance. In addition, 3 out of the 4 miscarriages in the GnRH agonisttreated group occurred during the second trimester. Nevertheless, as the authors put it, 'the trend was evident'. This 'trend' toward lower spontaneous abortion rates for laparoscopic therapies has support from other studies as well. In his series, Gjrnnaess reported early pregnancy loss in only 13 out of the 89 patients (14.6%) who conceived following laparoscopic electrocautery (Gjrnnaess, 1989). Similarly, Abdel Gadir et al reported early pregnancy loss in 3 out of 14 (21.4%) patients randomized to undergo laparoscopic ovarian electrocautery. In contrast, 8 out of 15 (55.4%) in the hMG group and 4 out of 10 (40%) in the pure FSH group of the same study aborted spontaneously (differences not statistically significant) (Abdel Gadir et al, 1990b). M E C H A N I S M OF A C T I O N The mechanism(s) responsible for the ovulation-inducing properties of ovarian diathermy have as yet to be satisfactorily elucidated. Nevertheless, there is no shortage of proposed mechanisms. Hormonal alterations that have been observed include marked decreases in circulating levels of androgens (specifically androstenedione and testosterone) as well as decreases in the circulating levels of oestradiol. LH secretion is also altered, with reductions noted both in concentrations of immunoreactive LH as well as in LH bioactivity. Transient increases in circulating levels of FSH have also been noted in some studies (see Table 2). The most widely accepted putative mechanism can be summarized as follows. Destruction of either ovarian stromal elements, or release of androgen-rich follicular fluid as subcapsular cysts are punctured, causes a fall in local and circulating levels of androgens. This fall creates a decrease in substrate for follicular aromatase, which, in conjuction with damage to the follicle walls themselves, produces a fall in circulating oestradiol levels. The fall in oestradiol levels releases the pituitary from both the negative feedback effects of oestradiol on FSH secretion and the positive feedback effects on LH secretion. These changes ultimately result in normalization of the LH/FSH ratio and allow follicular development to proceed to ovulation. That this alteration in feedback occurs, at least in part, at the level of the pituitary has been demonstrated. Pituitary LH secretion in response to infusions of GnRH is decreased post-operatively compared with the preoperative reponse, an effect that became more pronounced later in the postoperative period (Sumioki et al, 1988; Rossmanith et al, 1991). The concept of a decrease in LH activity being central to the success of these procedures makes sense, in that Abdel Gadir et al have demonstrated that ovulation rates and the continuation of ovulatory cycles are best when LH levels are high pre-operatively (Abdel Gadir et al, t993). In nonresponders, or those responders who returned to their anovulatory condition within a few cycles, LH levels did not change post-operatively or quickly

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returned to their pre-operative levels. Lapp6hn and Bogehelman (1989) showed that, in the case of BOWR, pregnancy was more likely to occur when the ovarian stroma resected was hyperplastic. In a similar vein, Keckstein found that pregnancy was more likely to occur when the follicular fluid at time of surgery was high in androgen content (Keckstein et al, 1990). While some of these methods (i.e. ovarian electrocautery) seem to produce a substantial reduction in the ovarian stroma, other methods that would seem to have a minimal (if any) effect on the stroma seem to produce similar effects upon ovulatory function. As early as 1938, Zondek reported the performance of multiple follicular puncture of polycystic ovaries through the cul-de-sac in 40 cases (Zondek, 1938). More recently, Mio et al (1991) described the use of transvaginal ultrasound-guided follicular aspiration to produce ovulation in the PCOS setting. Using a technique similar to that employed in in vitro fertilization programmes, all follicles persisting after three anovulatory cycles were punctured and thoroughly aspirated. Successful ovulation was observed in 7 out of 8 (87.5%) patients and in 20 out of 38 (52.6%) cycles. Four of the 8 patients (50%) conceived. There were 10 patients with sonographic evidence of polycystic ovaries but without hormonal alterations: ovulation occurred in all 10 of the patients and in 50 out of 79 (63.3%) cycles. Five out of the 10 (50%) patients in this category conceived. Other mechanisms thought to be important include the concept that the hyperaemia associated with the post-operative healing process may play a role by increasing the delivery of gonadotrophins to the ovary (Greenblatt and Casper, 1987). The observed decreases in inhibin concentration observed in the immediate post-operative period would seem too transitory to explain the long-term effects. Numerous investigators have proposed that local intraovarian (i.e. paracrine) factors may produce the observed effect. However, a small but important study by Balen and Jacobs (1994) demonstrated that the side on which ovulation occurred after the operation was randomly distributed, even when only one ovary was treated. Thus one can surmise that whatever the effects are at the ovarian level, the mechanism responsible for ovulation seems to exert itself through systemic routes.

MEDICAL TREATMENT OPTIONS FOR CLOMIPHENE CITRATE-RESISTANT SUBJECTS Conventional gonadotrophin therapy The use of gonadotrophins in the anovulatory PCOS patient who has failed to ovulate on clomiphene citrate is well established. The combination of gonadotrophins and human chorionic gonadotrophin (hCG) stimulates ovarian follicular maturation, resulting in a high rate of ovulation and sixcycle cumulative pregnancy rates of 50-70%. Spontaneous abortions occur in 24-39% of conceptions (Wang and Gemzell, 1980).

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While the above disadvantages may be acceptable for a pregnancy rate of 50-70%, those overall pregnancy rates may not be representative of outcomes for PCOS subjects. Dor et al (1980) noted a 91.2% cumulative pregnancy rate after six cycles of therapy in hypo-oestrogenic subjects. However, it required 12 cycles of therapy to achieve even a 50% cumulative pregnancy rate in eu-oestrogenic subjects who had failed clomiphene citrate therapy. Likewise, Fluker et al (1994) reported 6-month cumulative pregnancy rates of 89% in hypo-oestrogenic subjects and 63% for eu-oestrogenic nonnoandrogenic subjects, but only 30% in euoestrogenic subjects with elevated androgen levels. In summary, while gonadotrophin therapy is very effective in the hypogonadotrophic, hypo-oestrogenic subject, or the eu-oestrogenic subject with normal androgen levels, it appears much less effective in the setting of PCOS. Moreover, it has significant drawbacks, including its high cost and its intensive monitoring requirements, together with potentially serious medical complications, such as a multiple gestation rate of about 30% and a small but real potential for ovarian hyperstimulation syndrome.

Pulsatile GnRH therapy Reported ovulation rates with pulsatile GnRH in PCOS patients are generally in the 40-60% range (Martin et al, 1990), comparable to gonadotrophin therapy, with the advantage that most ovulatory cycles are monofollicular. In an effort to normalize the pre-treatment endocrine milieu, Filicori et al (1991) utilized pulsatile GnRH therapy combined with a 6-8 week period of pre-treatment with a GnRH agonist. They reported improvements in the rates of ovulation (76%) and pregnancy (28% per cycle) with this combination therapy. Unfortunately, the spontaneous miscarriage rates have remained high (43%).

Combined GnRH agonist-gonadotrophin therapy The addition of GnRH agonists in an effort to decrease the levels of endogenous LH prior to beginning gonadotrophin therapy has been described (Fleming et al, 1982, 1985; Buckler et al, 1989). The reduction in LH was thought to confer a greater margin of safety where OHS was concerned and might improve pregnancy rates by creating a more favourable hormonal environment for oocyte maturation. It might even allow involution of the hypertrophied stromal compartment. Results of randomized studies, however, have not demonstrated any distinct advantages in terms of pregnancy rate or decreased ovarian sensitivity to gonadotrophin therapy with the addition of GnRH agonists (Buckler et al, 1989; Kupferminc et al, 1991). It is difficult therefore to recommend the routine use of GnRH agonists for PCOS patients.

Low-dose gonadotrophin therapy Brown in 1969 first suggested the use of a low starting dose of

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gonadotrophin with small stepwise increases to encourage monofollicular development (Brown et al, 1969). Capitalizing on this concept, Polson et al were able to induce ovulation successfully in all of 10 patients to whom low-dose 'pure' FSH was administered in subcutaneous pulses. Five out of the 10 patients subsequently conceived. Seventy-two per cent of the patients experienced ovulatory cycles, with 78% of these cycles being unifollicular. The 6-month cumulative conception rate was 55% (Polson et al, 1987). In 1989, the same authors concluded that daily intramuscular injections of FSH were effective as the subcutaneous pulsed route of administration (Polson et al, 1989). Since then, it has been demonstrated that the low-dose regimen works equally well with FSH or hMG (Sagle et al, 1991). At present, the low-dose gonadotrophin regimen, with its lower risk of multiple gestation and hyperstimulation, appears to be the most promising of the medical treatments now available. L A P A R O S C O P I C VERSUS M E D I C A L T R E A T M E N T Gj6nnaess has recently proposed that laparoscopic electrocautery be the first-line treatment for all PCOS patients undergoing laparoscopy for any reason, even if pregnancy is not desired at that time (Gj6nnaess, 1994). His reasons are based on his large personal experience with the procedure. He has noted that the majority of patients continue to have ovulatory cycles for up to 10 years following ovarian electrocautery. Where anovulatory PCOS is the only identified barrier to conception, pregnancy has occurred in more than 89% of subjects. Those patients who underwent the procedure and used oral contraceptives for up to 2 years afterwards seemed to have had little trouble conceiving spontaneously once their contraception was discontinued. While the considerable experience of Gj6nnaess should not be discounted, case series should not be given the same weight as controlled studies. When evaluating the efficacy of a given therapy, controlled studies are required. The uncontrolled case series present in the literature do not provide evidence of efficacy or safety. Admittedly, these studies do provide compelling preliminary evidence to the effect that these procedures may be comparable (or even superior) to currently available methods of medical ovulation induction for that small subgroup of PCOS subjects whose anovulation proves resistant to clomiphene citrate therapy. However, it is important to keep in mind the fact that surgical methods of ovulation induction do seem to produce adnexal adhesions, which may carry with them the risk of permanent impairment of fertility. Also, the one report of ovarian atrophy (Dabirashrafi, 1989) shows that these procedures are not risk-free. Furthermore, we know little about the long-term effects of this therapy on issues such as age of menopause or risk of ovarian cancer. Until a systematic study is performed that demonstrates little or no risk of reproductive impairment, we consider that the laparoscopic procedures should be reserved for those patients unresponsive to clomiphene citrate therapy who can not or do not wish to undergo gonadotrophin therapy.

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At the present time, we consider that clomiphene citrate should remain the first line of treatment for the chronic anovulation that accompanies PCOS. Clomiphene citrate is relatively inexpensive and produces ovulatory cycles in a high proportion of chronically anovulatory patients. It can be safely used with minimal monitoring requirements. Furthermore, the risks of high-order multiple gestation and ovarian hyperstimulation are low. The clinician can expect 60-85% of patients to ovulate on standard clomiphene citrate regimens, and 40-50% of patients will conceive (Garcia et al, 1977; Nunley et al, 1985). While conception rates may be lower in PCOS patients than for other subgroups of chronically anovulatory subjects (Regan et al, 1990), and while some studies (Whitelaw et al, 1970; Garcia et al, 1977; Hammond and Talbert, 1982) show an increased rate of early pregnancy loss in clomiphene citrate-induced pregnancies, others (Kistner, 1965; Adashi et al, 1979) have not found such an association. In any event, the probability of an eventual live birth is high. Importantly, we know of no increased potential for intra-abdominal adhesion formation or other permanent impediments to fertility from the use of this medication. PATIENT S E L E C T I O N FOR LAPAROSCOPIC O V U L A T I O N INDUCTION For the patient who presents with bona fide failure of treatment with clomiphene citrate, the choice of treatments rests between medical ovulation induction using gonadotrophins and the use of a laparoscopic surgical method. This choice of course implies that a complete infertility evaluation and an adequate effort at ovulation induction with clomiphene citrate have been carried out prior to considering surgical ovulation induction. Little is known for certain regarding the mechanism of action whereby these procedures exert their ovulation-inducing properties. Furthermore, there are no long-term data available with which to evaluate the effect on health in general. In our opinion, until more is known, the physician who performs these procedures under the guise of 'since we are doing a laparoscopy anyway, we might as well "treat" your ovaries' may well do the patient a great disservice. A careful search for other causes of infertility is imperative because the presence of additional infertility factors will significantly influence the post-operative pregnancy rates. Gj6nnaess gives data on 138 subjects who had no infertility factors other than the anovulation due to PCOS. Of the 138 patients in this group, 123 (89.1%) conceived. Where a second adverse factor to fertility was present, only 29 out of 81 (36%) conceived (Gj6nnaess, 1994). In one of his earlier papers, Gj6nnaess showed that where an added tubal factor was present, only 3 out of 21 (14%) conceived and only 2 out of 7 (29%) with an oligospermic male partner conceived (Gj6nnaess, 1990). Similarly, in Armar et al's (1990) study, only 1 out of 5 (20%) patients who ovulated post-operatively conceived when endometriosis was present, while 7 out of 8 (87.5%) with normal pelvic anatomy conceived. In Verhelst et al's (1993) study, if the 2 patients with oligo-

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spermic partners were excluded, 11 out of 13 (84.6%) conceived. Thus it would appear that in the absence of other adverse factors, pregnancy rates can approach those seen in the best of the BOWR experience, while those patients with additional infertility factors may be better served by established treatments for those conditions. An evaluation of the pre-treatment hormonal milieu would seem helpful in selecting patients for surgery. Those patients with elevated LH levels (commonly regarded as /> 10 IU/ml) seem more likely to conceive postoperatively (Abdel Gadir et al, 1991), while those patients not experiencing a post-operative fall in circulating LH levels were the ones who failed to ovulate following surgery. Likewise, early resumption of the anovulatory state was associated with a return to the pre-treatment hormonal milieu, while no such regression was noted for persistently ovulatory subjects (Abdel Gadir et al, 1993). Gj6nnaess has shown that the overweight patient experiences a lower rate of ovulation than does the patient of normal body weight (Gj6nnaess, 1994). Smoking has also been shown to adversely affect pregnancy rates in this group of patients (Naether et al, 1993). SUMMARY Notwithstanding the shortcomings of the available data, this review of the available literature strongly suggests some real benefits of laparoscopic treatment for carefully selected patients who fail clomiphene citrate therapy. While we very cautiously endorse a place for this procedure in the armamentarium of the clinician, we would like to state emphatically that this procedure has not been shown to be free of risks to the fertility status of women. The notion that this procedure is not associated with adhesion formation is false, and the reports of ovarian atrophy, while rare, are also of serious concern. These issues, as well as the cost and risk associated with any operative procedure, underscore the importance of performing this operation only when all other available options have been exhausted. It is, in our opinion, a great disservice to the patient to perform laparoscopic equivalents of ovarian wedge resection after only a cursory infertility evaluation and a brief attempt at clomiphene citrate ovulation induction. Until it can be conclusively shown that laparoscopic ovulation induction does no harm to fertility potential or to long-term health, these procedures should be used when all available non-invasive options have been explored. REFERENCES Aakvaag A & Gj6nnaess H (1985) Hormonal response to electrocautery of the ovary in patients with polycystic ovarian disease. British Journal qf' Obstetrics and Gynaecology 92, 1258-1264. Abdel Gadir A, Alnaser HMI, Mowafi RS & Shaw RW (1992) The response of patients with polycystic ovarian disease to human menopausal gonadotropin therapy after ovarian electrocautery or a luteinizing hormone-releasing hormone agonist. Fertility and Sterility 57:30%313. Abdel Gadir A, Khatim MS, Mowafi RS et al (1990a) Hormonal changes in patients with polycystic ovarian disease after ovarian electrocautery or pituitary desensitization. Clinical Endocrinology 32: 749-754.

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