The enigma of polycystic ovary syndrome by kjarFd

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    The Enigma of Polycystic Ovary Syndrome – Is There a Place for Ovarian
                                      Surgery?
                                       S. Daya
 Departments of Obstetrics and Gynecology and Clinical Epidemiology & Biostatistics,
                    McMaster University, Hamilton, Ontario, Canada
Polycystic ovary syndrome (PCOS) is a relatively common clinical disorder that affects 5

– 10 % of women in the reproductive age group. The disorder is associated with a wide

spectrum of presenting features including anovulation, infertility, obesity, hirsutism,

insulin resistance and dyslipoproteinemia. A fairly consistent finding on ultrasonography

is enlargement of the ovaries with more than 10 sonolucent cystic structures, 2 – 8 mm

in diameter scattered around an echo-dense thickened central stroma (1).

Problems in inducing ovulation in PCOS are well recognized and range from a brisk

response to no response at all. Obesity, even of moderate degree (BMI>27kg/m²) is

associated with a reduced likelihood of ovulation. Thus, exercise and calorie restriction

to reduce weight are necessary to optimize the success rate with medical therapy.

There is also increased interest in the use of insulin sensitizing drugs to induce

ovulation. However, it is not clear whether the observed benefit can be attributed to the

medication or to the resulting weight loss.

The drug of choice to induce ovulation is clomiphene citrate. It is an antiestrogenic

agent that displaces endogenous estrogen from hypothalamic and pituitary estrogen

receptor sites thereby reducing the negative feedback, resulting in an increased pulstile

secretion of gonadotropin-releasing hormone (GnRH). The resulting rise in follicle

stimulating hormone (FSH) that induces follicular growth is also accompanied by an

equally large increase in serum luteinizing hormone (LH) concentration that may persist

into the latter stages of the follicular phase of the cycle. Hypersecretion of LH is

association with a lower likelihood of pregnancy and higher rate of miscarriage.



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Nevertheless, high rates of ovulation (60 – 85%) and acceptable rates of pregnancy (30

– 40%) are seen with clomiphene citrate use, with most pregnancies occurring within 6

cycles of treatment. The reason for the failure to ovulate in the remaining 15 – 40% of

anovulatory women who do not respond to clomiphene citrate is not clear.

Gonadotropin Therapy

Failure to ovulate after 2-3 successive cycles of clomiphene citrate at the maximal dose

is usually an indication to consider treatment with gonadotropins. Advances in

purification techniques have witnessed a progression in gonadotropin availability from

menotropins to urofollitropins to the currently available follitropins. Women who respond

normally to clomiphene citrate but fail to conceive after 6 to 12 cycles of treatment are

also considered candidates for gonadotropin therapy. A variety of treatment regimens is

available, but the low-dose, step-up regimen appears to produce optimal results with

high cumulative pregnancy rates (62% after 6 months and 73% after 12 months of

treatment) (2). The major risks associated with gonadotropin therapy are ovarian

hyperstimulation syndrome (OHSS) and multiple pregnancy, both of which can be

reduced with more careful monitoring with transvaginal ultrasonography and

measurement of estradiol levels.

Surgical Therapy

Bilateral ovarian edge resection was first introduced as treatment for patients with

anovulatory PCOS (3). This operation restored menstruation in all cases, and 2 out of 7

women became pregnant. Until the introduction of clomiphene citrate in 1962, this

surgical approach was the only treatment available for women with anovulatory PCOS.

The ovulation rates were high but pregnancy rates were much lower, probably because




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of the high incidence of post-surgical periadnexal adhesion formation which converted

an endocrinological problem to a mechanical one.

Laparoscopic Ovarian Drilling

This technique was first described in 1984 and involved the creation of 8 – 15 holes,

each one 2 – 4mm deep on the surface and stroma of each ovary using a unipolar

electrode at 300 – 400 W for 2 – 4 seconds (4). Several modifications of the technique

have been reported including the use of laser (CO2, argon, KTP or Nd-YAG) with good

results. However, the published results of laser surgery are inferior to those of

electrocautery. Ovulation rates of 70 – 92% and pregnancy of rate of 70% have been

reported. The use of an insulated needle for cautery was recently reported to be

associated with minimal amount of adhesion formation in the small sample of patients

who underwent a second-look laparoscopy (5). The technique involves inserting an

insulated needle perpendicularly to the ovarian surface, entry being aided by a short

duration of cutting current of 100 W. The whole length of the needle (8mm) is inserted

into the ovary and activated with 40 W coagulating current for 2 seconds at each point.

After making 10 – 15 punctures per ovary, the surface of the ovary is lavaged and 500 -

1000 ml of crystalloid solution is left in the peritoneal cavity.

Mechanism of Action of Laparoscopic Ovarian Drilling

The mechanism of action is unknown but is believed to be related to endocrine changes

that result from the procedure. A significant reduction in androgen (testosterone and

androstenedione) levels in the serum has been observed (6,7). A transient increase in

LH in the first 24 to 48 hours after surgery is followed by a decrease in serum LH

concentration (8). The decrease is mainly in pulse amplitude rather than pulse




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frequency (9) suggesting an endocrine effect at the level of the pituitary gland rather

than the hypothalamus. First ovulation after surgery occurs randomly involving either

ovary even in patients with unilateral ovarian cauterization (10). The size of the ovary

does not affect the response to the ovarian cauterization; similar decreases in LH, FSH,

DHEAS and testosterone levels were observed in women with normal (ovarian volume

< 8cm³ or cross-sectional area < 10cm²) or enlarged ovaries. (11) These observations

strongly indicate that the effect of surgery is mediated via a central mechanism rather

than a direct effect on the treated ovary.

Interestingly, glucose utilization and plasma insulin concentrations during an

euglycemic-hyperinsulinemic clamp did not change after laparoscopic ovarian

cauterization (7). In addition, no significant changes were observed for cholesterol,

triglycerides and apolipoprotein concentrations (7).

Potential Risks and Complications of Laparoscopic Ovarian Drilling

Intra-operative complications from the surgical procedure are rare and include avulsion

of utero-ovarian ligament from excessive traction and bleeding from the holes drilled in

the ovary (12). Other risks are associated with the laparoscopy procedure itself and are

increased with obesity, a condition commonly encountered in women with PCOS. Peri-

adnexal adhesions are problematic because of their higher incidence. Unfortunately, the

risk of adhesion formation has not been ascertained accurately because there is no

standardized follow-up protocol that involves second-look laparoscopy for all patients at

a specified time after the initial surgical procedure. Based on case series reports, the

incidence of adhesion formation has ranged from 0 – 100%, with the risk being higher

when laser is used compared to electrocautery (2). It has been suggested that adhesion




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formation can be reduced by minimizing injury to the ovarian surface by restricting the

number of punctures, using an insulated needle, activating the coagulating current only

after the needle is inside the ovarian stoma and irrigating the peritoneal cavity at the

end of the procedure (8).

Another potential complication is premature ovarian failure. However, the theoretical

possibility of this complication awaits long-term follow-up studies evaluating the effect of

ovarian drilling on the age at which menopause occurs.

Comparative Efficacy of Ovarian Drilling and Gonadotropin Stimulation

The increasing interest in surgical treatment if PCOS has been fuelled by the

widespread availability and use of operative laparoscopy. The rationale for the surgical

approach is the same as when ovarian wedge resection was introduced i.e. reduction of

ovarian androgen levels so that follicular development can take place by avoiding the

atresia that results from excess androgens. However, the efficacy of this procedure for

ovulation induction and pregnancy has to be compared against the standard therapy

such as gonadotropins in women with PCOS resistant to clomiphene citrate. To date,

there have been four randomized trials addressing this question (13 – 16). The studies

all employed bilateral ovarian electrocautery and compared this intervention with three

(15) to at least six cycles (13, 14, 16) of gonadotropin stimulation. In 3 of the 4 trials, the

sample sizes were small, ranging from 29 to 56, whereas in the largest trial (16) the

sample size was 168. High rates of ovulation were observed in all trials. Regarding

pregnancy rates, there was significant heterogeneity of treatment effect, primarily from

one study in which there was a non-significant beneficial effect with ovarian

cauterization (13). The other three studies all showed benefit in favour of gonadotropin




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stimulation, the effect being statistically significant only in one trial (16). Overall, the

common odds ratio using the random effects model was 0.66 (95% confidence interval,

(CI) 0.16 – 2.75).(figure 1)

Although the overall pregnancy rates were similar in the two groups in the largest trial

(68% became pregnant after 6 cycles with gonadotropins and 74% became pregnant

after 12 cycles in the ovarian drilling group), the surgically treated group was

deliberately contaminated by ovulation induction with clomiphene citrate in some

women and recombinant FSH in the rest who did not conceive (16). When comparing

the two groups without contamination, it is clear that the pregnancy rate is much higher

on a per cycle basis with gonadotropins; after three cycles, the cumulative pregnancy

rate was almost twice as high with gonadotropins and continued to rise, whereas, it

levelled off in the surgical treatment arm (17), At 6 months, the cumulative ongoing

pregnancy rate was 37% in the ovarian cautery group and 68% with gonadotropins

(relative risk 0.54, 95% CI 0.39 – 0.76) (17). The rate of spontaneous abortion was not

different in the two groups (OR = 0.54, 95% CI 0.20-1.47).(figure 1) No multiple

pregnancies were observed among patients treated with ovarian drilling compared with

gonadotropin stimulation (OR=0.16, 95% CI 0.04-0.67). (figure 1)

Long Term GnRH Analogue Versus Ovarian Drilling

The belief that elevation of LH is implicated in the pathophysiology of PCOS led to the

idea that normalizing the LH concentration could have a positive effect on this disorder

(18) Recently, a prospective study was undertaken to compare the efficacy of medical

treatment with GnRH analogue and surgical treatment using ovarian drilling in women

with PCOS, unresponsive to clomiphene citrate (19). The protocol in the medical group




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involved down-regulation with GnRH analogue for 6 months together with add-back

therapy with an oral contraceptive. The surgical group underwent laser drilling of both

ovaries with a CO2 laser. Each group then underwent treatment for up to three cycles

with a low-dose, step-up stimulation regimen with recombinant FSH. Both groups had

similar hormonal profiles and ovulation occurred with similar frequencies. Although the

sample size was small, the pregnancy rates per patient were similar in the two groups.

Thus, long term treatment with GnRH analogues appears to be as successful as

laparoscopic laser cauterization.

Summary

In women with clomiphene resistant PCOS, the options of using gonadotropins or

ovarian drilling with electrocautery both result in ovulatory cycles and pregnancy.

However, the surgical intervention is not as efficacious as ovulation induction with

gonadotropins, unless the two interventions are used sequentially. Hormonal profiles

after ovarian electrocautery demonstrate a reduction in the levels of LH, testosterone,

DHEAS and androstenedione, but glucose utilization did not change indicating that

insulin sensitivity is not improved. Insulin resistance is believed to be a major factor in

the persistence of anovulation in women with PCOS. The inability of ovarian

cauterization to affect insulin sensitivity may, in part, explain the lower efficacy of this

approach. Another reason may be the higher likelihood of developing periadnexal

adhesions following surgery, and adverse effect that may be reduced with less

traumatic techniques. Thus, based on the evidence available to date, the value of

ovarian surgery as a treatment of women with clomiphene citrate resistant PCOS is




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questionable and should only be considered as a last resort after all other options,

including gonadotropin stimulation and GnRH analogue down-regulation, have failed

References

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      al. Multifollicular ovaries: Clinical and endocrine features and response to

      pulsatile gonadotropin – releasing hormone. Lancet 1985; 2:1375-1378.

   2. Balen AH, Braat DDM, West C. Cumulative conception and live birth rates

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   3. Stein IF, Cohen MR. Surgical treatment of bilateral polycystic ovaries. Am

      J. Obstet Gynecol 1939; 38:465-473.

   4. Gjonnaess H. Polycystic ovarian syndrome treated by ovarian

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     insulin sensitivity or lipid – lipoprotein levels. J Clin Endocrinnol Metab

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     (abstract).




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   15. Farquhar CM, Williamson K, Gudex G, Johnson N, Garland J, Sadler L. A

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   19. Muenstermann U, Kleinstein J. Long-term GnRH analogue treatment is

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Figure 1. Outcomes from comparative evaluation of laparoscopic ovarian cauterization
             and gonadotropin ovulation induction.




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