Long-term GnRH analogue treatment is equivalent to laparoscopic laser diathermy in polycystic ovarian syndrome patients with severe ovarian dysfunction

U. Muenstermann1 and J. Kleinstein

Department of Reproductive Medicine and Gynaecologic Endocrinology, University of Magdeburg, D-39108 Magdeburg, Germany


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This prospective, randomized study included 18 polycystic ovarian syndrome (PCOS) patients with severe ovarian dysfunction, who were evaluated by standard clomiphene and FSH stimulation. In this group of patients, a 6 month down-regulation with gonadotrophin-releasing hormone (GnRH) analogues gave outcomes similar to laparoscopic ovarian laser diathermy with respect to stimulatory outcome and pregnancy rate. Clomiphene stimulation with 50 mg of clomiphene/day and FSH stimulation in a low-dose, step-up protocol with purified FSH did not result in oligofollicular development; thus patients were divided into two subgroups: one subgroup received laparoscopic laser drilling and the other received 6 months of therapy with GnRH analogues plus add-back therapy after diagnostic laparoscopy. Subsequently, three cycles of low-dose, step-up stimulation with recombinant FSH were started. In both groups, ~30% of cycles still remained anovulatory. In the down-regulated subgroup, this mainly happened in the first cycle. In each group, ovulation was achieved in 14 cycles, intrauterine insemination was performed, and five pregnancies were obtained. This resulted in a pregnancy rate of 36% per ovulatory cycle in both groups. Overall, 50% of the formerly unreactive patients in both groups overcame childlessness. In achieving this, long-term treatment with GnRH analogues was as successful as laparoscopic laser diathermy.

Key words: clomiphene stimulation/GnRH analogues/laser diathermy/polycystic ovarian syndrome


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Polycystic ovarian syndrome (PCOS) remains an incompletely understood entity, characterized by oligomenorrhoea, anovulation and typical biochemical and clinical features. Given that the presenting symptom of these patients often is infertility, the restoration of ovulatory function assumes paramount importance. Usually low dosage clomiphene citrate is the treatment of first choice, although it is known that 20% of women will not respond to this treatment (Garcia et al., 1977Go; Gorlitsky et al., 1978Go). Because of its anti-oestrogenic effects, an increasing dosage of clomiphene citrate will lead to thickening of the cervical mucus and failure of endometrial development. Therefore, patients resistant to clomiphene citrate medication will usually be treated with exogenous gonadotrophins. Results of gonadotrophin treatment, with both human menopausal gonadotrophin and FSH, in PCOS are often reported to be disappointing due to low ovulation and cycle fecundity rates. In our clinic 33% of patients not susceptible to clomiphene citrate treatment did not show an appropriate response to FSH stimulation in the low-dose, step-up protocol, either because of failure of follicular development, or because of multifollicular growth. Moreover, raised chances of multiple gestation and an elevated risk of ovarian hyperstimulation syndrome have been described (Wang and Gemzell, 1980Go). To give patients resistant to clomiphene and FSH stimulation an option to ovulate, different approaches are being discussed.

Usually, ovarian surgery, e.g. wedge resection, electrocautery or laser drilling, is used in patients not responding sufficently to medical therapy. Although satisfying ovulatory rates of 90% can be achieved, 25–50% will have mild to moderate postoperative abdominal adhesion formation, which is again associated with lower conception rates (Donesky and Adashi, 1995Go).

It is stated that LH elevation plays an important role in the pathophysiology of PCOS (Berga, 1994Go). Down-regulation with GnRH agonists can relieve the LH impact on folliculogenesis by normalizing LH concentrations and LH/FSH ratio (Goni et al., 1994Go) and is therefore thought to improve the outcome of stimulation. No data are available to compare the results of medical and surgical treatment. Each method has been intensively evaluated by itself with usually good results in certain patient subgroups. Nevertheless, no randomized trial has yet compared surgical with medical treatment and therefore a prospective, randomized study was conducted to compare laparoscopic ovarian laser drilling to long-term down-regulation with GnRH analogues.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients
Between August 1996 and April 2000, 86 patients who attended our clinic for infertility treatment were newly diagnosed with PCOS. PCOS was characterized by hormonal findings of elevated androgens, LH and LH/FSH ratio (>1.8). The patients showed increased body mass index (BMI), oligomenorrhoea (cycle length >35 days) or amenorrhoea (<3 menstruations per year) and typical findings on sonography, such as increased ovarian volume (>8.0 cm3), increased ovarian area (>5.5cm2) and more than 11 subcapsular follicles <10 mm on a cross-sectional cut (Pache et al., 1992Go). Other endocrinological abnormalities, such as hyperprolactinaemia or thyroid dysfunction, were ruled out. Patients with tubal disease diagnosed by laparoscopy or partners with male subfertility were excluded from the study. All patients were stimulated with clomiphene and, consecutively, with FSH, if clomiphene stimulation showed no follicular growth. Eighteen patients showed no oligofollicular growth on standard clomiphene and FSH stimulation as described below and were subsequently evaluated for further infertility treatment. They were prospectively randomized by submitting them alternately to medical treatment with GnRH analogues with add-back therapy (group A) and surgical treatment by endoscopic laser diathermy with a CO2 laser (group B). They formed the study group whose results are reported here.

To characterize the patients, BMI, waist/hip ratio, hormonal profile and ovarian volume were recorded (Table IGo).


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Table I. Main characteristics of 18 polycystic ovarian syndrome patients with severe ovarian dysfunction
 
Treatment protocol
Standard clomiphene challenge test was carried out by administering 50 mg clomiphene citrate (Clomhexal 50; Hexal, Holzkirchen, Germany) from day 5 to day 9 after induced or spontaneous menstruation. Vaginal ultrasound was performed on day 11. If no follicular growth >12 mm was detected, ultrasonography was again applied 4–7 days later. Patients were termed `clomiphene resistant' if still no leading follicle could be seen on day 18 to day 21 of the cycle after the application of 50 mg of clomiphene citrate. By not intensifying clomiphene treatment, the aim was to select a patient subgroup with more severe ovarian dysfunction. With respect to the negative side-effects of clomiphene, e.g. higher abortion rate and reduced endometrial thickness (Dickey et al., 1993Go), the more modern method of ovarian stimulation with FSH was preferred for these patients.

FSH challenge was performed by daily application of purified FSH (Fertinorm HP 75; Serono, Unterschleißheim, Germany), that started on day 3 of the cycle. Again, vaginal ultrasonography was performed 7 days later. If follicular growth >12 mm could be seen, stimulation was continued with the same dosage. Otherwise, dosage was increased by 1/2 ampoule Fertinorm HP 75 to 112.5 IU/day. Stimulation was continued for 4–7 days and again an increase of dosage (+37.5 IU/day) was carried out according to folliculometry. Only if no follicular development could be achieved by day 21 of the cycle were patients labelled FSH negative for conservative infertility treatment.

Laparoscopy was performed on all patients after negative clomiphene and FSH response. Randomization was performed by alternately submitting patients to two different treatment protocols. Patients 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 received chromopertubation and laparoscopic laser drilling with a CO2 laser (power density 105 W/cm2). With this treatment, all visible, subcapsular small follicles were opened by the laser beam (range 10–30 follicles/ovary). The effect was controlled by the outflow of the follicular fluid. Both ovaries were treated in all patients. To avoid adhesion formation, extensive pelvic lavage was performed and an artificial ascites with 500 ml 10% dextran solution (Infucoll M40, molecular weight 40 000; Serumwerke Bernburg, Germany) was installed. On the third post-operative day, hormonal values were measured.

Patients 1, 3, 5, 7, 9, 11, 13, 15, 17 and 19 received diagnostic laparoscopy with chromopertubation. Afterwards, treatment with GnRH analogues (Enantone Gyn; Takeda Pharma, Aachen, Germany) and add-back therapy with Diane 35 oral contraceptive (Schering, Berlin, Germany) was commenced for 6 months.

After laser drilling, stimulation for intrauterine insemination (IUI) was started on the first spontaneous postoperative cycle. On the other hand, in patients with GnRH analogue treatment, induced menstruation due to the add-back therapy was used as a starting point for stimulation. All patients began on cycle day 3 with recombinant FSH (rFSH) at a starting dose of 50 IU/day (Puregon; Organon, Oberschleißheim, Germany) for stimulation. Vaginal ultrasound was performed on day 10. If there was follicular growth >12 mm in diameter, rFSH was continued until human chorionic gonadotrophin (HCG) injection (Pregnesin, 5000 IU; Serono). If there was no follicle >12 mm, rFSH dosage was increased by 1/2 ampoule rFSH to 75 IU per day. Vaginal ultrasound was again applied after 4-7 days, and the decision of dosage augmentation was made again according to the results of folliculometry. In cases of successful stimulation, HCG was administered at a follicular diameter of 18-20 mm and IUI was performed 36 h later. Luteal phase was supported by administering 300 mg of progesterone (Utrogest; Dr Kade, Berlin, Germany). A maximum of three attempts of stimulation were carried out within 6 months.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 54 patients (63.1%) did not respond to clomiphene at a daily dosage of 50 mg. These patients were tested with FSH: 36 showed good follicular growth with low-dose, step-up FSH (67%), and the remaining 18 showed no reaction to FSH (33%).

The main characteristics of patients in groups A and B are shown in Table IGo. They suffered mainly from primary infertility. Only in a few cases (one in group A, three in group B) was secondary infertility diagnosed. Mean duration of infertility was >3 years in both groups, minimizing the impact of non-treatment pregnancies. BMI, waist/hip ratio and ovarian volume were similarly elevated in both groups. Their hormonal profiles did not differ concerning LH, LH/FSH ratio and androgen concentrations.

Patients in group A completed 21 stimulation cycles (2.63/patient) after treatment with GnRH analogues, with a mean of 25 ampoules of FSH (50 IU)/stimulated cycle. Dosage was not significantly higher if stimulation was successful (27.2 versus 23.8 ampoules). All patients showed oligofollicular growth in at least one of three attempts (25% in the first cycle, 63% in the second cycle, 86% in the third cycle). Overall, 14 stimulation cycles (67%) resulted in HCG injection and five pregnancies were diagnosed (36% pregnancy rate/ovulation). All pregnancies occurred on the third attempt to induce ovulation. One miscarriage was observed, reducing live birth rate to 29%. Overall, 63% of the patients in group A experienced pregnancy and 50% had a healthy baby (Table IIGo).


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Table II. Results after 6 months of treatment with gonadotrophin-releasing hormone (GnRH) analogues and add-back therapy (group A) or laser diathermy (group B)
 
In group B, 20 stimulation cycles (2.0 per patient) with FSH after laser drilling were completed. Again, at least one of the maximal three attempts to induce ovulation was successful in each patient (first cycle 70%, second cycle 66%, third cycle 75%). An average of 20.5 ampoules of FSH (50 IU)/stimulated cycle was used. On 14 occasions times (70%) oligofollicular growth was diagnosed and HCG injected. Five pregnancies could be diagnosed (36% pregnancy rate if ovulation could be induced). Pregnancies occurred twice on the first, twice on the second and once on the third ovulatory cycle. As no miscarriage took place, the take home baby rate was 36%; 50% of all patients in group B experienced pregnancy and delivered a baby.

The results shown in Table IIGo revealed no statistically significant differences when comparing both groups.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Infertility is one of the main clinical problems to be solved for patients with PCOS. Many attempts have been made to characterize and define PCOS, some stressing biochemical parameters, others emphasizing clinical findings like sonography. The same diversity of opinions is found in trying to define the severity of the disease. Some authors have suggested that high LH concentrations indicate severe PCOS (Farhi et al., 1995Go), accounting for significantly lower rates of ovulation, fertilization and pregnancy, as well as high rates of miscarriage. Others believe that insulin resistance is an unfavourable condition for infertility treatment in PCOS (Dale et al., 1998Go). For the clinician, surely the failure to respond to standard stimulatory treatment will be the major challenge. Therefore, the aim of this study was to evaluate treatment modalities for patients not showing acceptable ovarian response to standard clomiphene and FSH stimulation.

Clomiphene citrate has been used to induce ovulation in patients with ovulatory disorders since 1962 and has replaced aggressive surgical techniques widely used in patients with PCOS. Despite good stimulatory response to clomiphene in 65–80% of PCOS patients, about one-third of patients will not show sufficient follicular growth even after high dosages of clomiphene of up to 200 mg per day. In our clinic, a high percentage (63.1%) were diagnosed clomiphene negative, probably due to the restriction to a dosage of 50 mg/day to avoid anti-oestrogenic uterine side effects. It is known that a higher dosage of clomiphene citrate can increase ovulatory responses, but not affect pregnancy rates. A daily dose of >100 mg of clomiphene citrate rarely confers any benefit and doses of 150 mg only worsen the side-effects, particularly of a thickened cervical mucus and anti-oestrogenic effect on the endometrium (Balen and Jacobs, 2000Go). Therefore, clomiphene stimulation was used, mainly in order to select a more severe PCOS subgroup, but not to achieve folliculogenesis at any price. Additionally it is known that women failing to respond to clomiphene show absence of folliculogenesis, despite an appropriate rise in FSH concentration (Lobo et al., 1982Go; Polson et al., 1989Go).

A variety of treatment modalities has been proposed in order to overcome the disadvantages of clomiphene. There is much evidence that supports the benefits of gonadotrophin stimulation with purified or, especially, rFSH. This is nowadays a relatively safe and uncomplicated treatment and should be offered ahead of surgical interventions in PCOS patients. Nevertheless, using the same working mechanism (to increase FSH concentrations) in the present study, only 67% of clomiphene resistant patients were susceptible to low-dose exogenous FSH. Due to economic considerations, rFSH was used only for patients after laser drilling or GnRH down-regulation, whereas otherwise purified FSH was applied. The similarity of both preparations, with respect to follicular maturation, oocyte quality and pregnancy rates is documented in the literature (Yarali et al., 1999Go).

If GnRH hypersecretion and LH-induced hyperandrogenaemia are aetiological features of PCOS, then those interventions which slow down LH pulsatility ought to restore normal ovarian function (Berga, 1994Go). As high LH concentrations not only cause lower rates of ovulation, fertilization and pregnancy, but also lead to higher rates of miscarriage (Homburg et al., 1988Go), normalizing of LH concentrations in PCOS patients is superior to exclusively endogenous or exogenous FSH stimulation. Two main therapeutic methods claim to interact with LH concentrations in PCOS patients: the medical method suggests long-term treatment with GnRH analogues, the surgical method is laparoscopic laser or electrocautery.

It has been shown that laparoscopic ovarian electrocautery is followed by a decrease in the pulse amplitude of LH secretion, with no change in the pulse frequency (Abdel Gadir et al., 1990Go). Treatment with GnRH analogues induced similar changes in the above study. Thus, both laparoscopic ovarian surgery and prolonged GnRH analogue treatment result in a reduced LH:FSH ratio, albeit through different mechanisms.

Surgical approaches have been applied to patients diagnosed with PCOS since the description of the syndrome by Stein and Leventhal in 1935 (Stein and Leventhal, 1935Go). Although favourable results could be achieved by the primarily used wedge resection, this technique was widely abandoned due to massive adhesion formation in one-third of patients (Buttram and Vasquero, 1975Go). Only in 1984 were surgical techniques revived, when Gjonnaess introduced laparoscopic electrocautery as a less extensive surgical technique (Gjonnaess, 1984Go). More recently, different laser vaporization techniques have been used successfully to induce spontaneous or stimulated ovulation in patients previously resistant to clomiphene citrate stimulation. Overall, 80–90% of patients will ovulate after ovarian cautery for PCOS and conception rates in the range of 45–66% are usually seen at 6–12 months thereafter (Casper and Greenblatt, 1990Go). As positive effects of either treatment seem to be time-limited in many patients (Genazzani et al., 1997Go), the decision was made to offer IUI to the patients in the study despite the absence of male subfertility. Additionally, the superiority of IUI over natural intercourse concerning pregnancy rates was shown in several studies (De Geyter et al., 1996Go)

Several potential mechanisms of action of surgical intervention to polycystic ovaries have been discussed. There was a suggestion that a reduction in ovarian androgen production, as consistently observed in all studies, results in a decline in LH secretion. This suggestion has been countered by the observation that, in a control group of non-PCOS patients, a similar reduction in the androgen concentration did not alter LH secretion (Gjonnaess and Norman, 1987Go). The predictors of an ovulatory response following surgery include prior responsiveness to clomiphene (Gjonnaess, 1984Go). As a result, 30% of cycles in the current study of clomiphene-resistant patients had to be cancelled after laparoscopic treatment. Nevertheless, all patients treated with laser vaporization showed stimulatory success at FSH stimulation in at least one of three cycles. Typical hormonal changes with decreased androstendione and testosterone after ovarian surgery are known and could also be seen in the present study. Additionally, a transient increase in LH and LH/FSH ratio, as seen in our patients after laser surgery, has been previously observed after electrosurgery for PCOS, stretching into a longer phase of reduced LH/FSH ratio (Naether et al., 1993Go). Ovulatory responses and pregnancies occurred in the first, second or third stimulation cycle, indicating stable ovarian responsiveness over the observed period of 6 months. Had there been sufficient follicular growth, a pregnancy rate of 36% and a live birth rate of 36% was achieved. Adhesion formation was not examined in the current study, but data suggest that less intensive surgery with only unilateral treatment or with very few subcapsular cysts opened shows similar results (Balen and Jacobs, 1994Go) compared to more extensive laser drilling. This could possibly further reduce the risk of adhesion formation.

Compared to the extensive literature on surgical treatment, less experience exists on treating PCOS patients with prolonged courses of GnRH analogues. Although it is counter-intuitive to treat patients wishing to become pregnant with GnRH analogues, prolonged pretreatment is known to suppress androgen concentrations and acutely improve rates of ovulation and conception in PCOS patients stimulated with pulsatile GnRH (Filicori et al., 1989Go). Nevertheless, the effect of 8 weeks GnRH pretreatment could not be maintained in that study for a consecutive second treatment cycle, again not showing ovulatory response to stimulation, indicating the need of a longer desensitization phase.

As plasma androgen concentrations increase with time, after terminating the suppression with GnRH analogues (Lemay and Faure, 1994Go), patients in the current study were not observed for spontaneous ovulatory cycles. Instead, they were encouraged to proceed to ovarian stimulation therapy, thus achieving the highest possible chance for pregnancy. Obviously, this rapid proceeding to stimulation after 6 months of down-regulation has the disadvantage of causing a high rate of stimulatory failure in the first cycle (75% as opposed to 30% after laser therapy). Higher rates of ovulatory success could be obtained in the following cycles, resulting in an overall ovulation rate of 67% and a pregnancy rate of 36%. All pregnancies occurred on the third trial of ovarian stimulation, dating 4–6 months after termination of down-regulation. This indicates a continuous positive effect of GnRH analogue therapy on ovarian function for at least 6 months. This might not be optimal during the first months after terminating down-regulation. There is some concern about the effect of prolonged oestrogen deficiency on bone metabolism. Indeed, 6 months of treatment with GnRH analogues can cause a small, reversible decrease in both forearm and spinal bone mineral content (Matta et al., 1988Go). Therefore a medium-dose oral contraceptive was included as add-back therapy. It has been shown in the past that long-term treatment with GnRH analogues, in combination with an oral contraceptive, can be successful in normalizing the hormonal milieu and ovarian volume in unselected PCOS patients (Genazzani et al., 1997Go). Although similar results could be achieved in the former study with oral contraceptive treatment alone, follow-up showed a quick return to the unfavourable pretreatment values and anovulatory cycles in the latter group. On the other hand, patients with combination therapy maintained ovulatory cycles and a favourable hormonal milieu for the 6 months of post-treatment observation.

Body weight is an important variable for the PCOS patients to respond to stimulation. The elevated insulin concentrations frequently encountered in obese women may negatively affect follicular function by increasing androgen concentrations. The persistence of anovulation in at least one cycle of most patients in our study and in ~30% of all cycles suggests a residual adverse effect on ovarian function caused by obesity (Pasquali et al., 1989Go).

According to the results of the present study, medical down-regulation with GnRH analogues can be an alternative to surgical procedures in patients with PCOS, who do not ovulate under clomiphene challenge and low-dose FSH stimulation. Fortunately, few anovulatory PCOS patients require ovarian surgery as ultimate therapy. But even these patients can be offered GnRH analogues as an alternative treatment. Therefore, there is still a need to individualize therapy for each patient. Surgical results are known to be best in non-smoking patients <35 years of age, of normal weight and with elevated LH and androgen concentrations (Donesky and Adashi, 1995Go). There is also evidence from the literature that surgical therapy has an advantage with respect to a lower abortion rate (Doneski and Adashi, 1995). On the other hand, especially in severely obese patients, laparoscopy can impose technical problems and significant anaesthesiological risks. Additionally, one has to bear in mind the essentially destructive character of surgical procedures on PCOS patients. Therefore, ultralong GnRH analogue therapy can be an option in the treatment catalogue.


    Notes
 
1 To whom correspondence should be addressed at: Department of Reproductive Medicine, University of Magdeburg, G-Hauptmann Str. 35, D-39108 Magdeburg, Germany.E-mail: Ursula.Muenstermann{at}yahoo.com Back


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 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on August 14, 2000; accepted on September 21, 2000.





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