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Therapeutic Strategies for Ovulation Induction in Infertile Women With Polycystic Ovary Syndrome

Posted on: Friday, 20 January 2006, 06:00 CST

By Cristello, Francesca; Cela, Vito; Artini, Paolo Giovanni; Genazzani, Andrea Riccardo

Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hirsutism, obesity, hyperandrogenism and insulin resistance. The syndrome is often accompanied by infertility because of anovulation. Many approaches have been proposed to solve this problem, with the most commonly used therapies being ovarian drilling and pharmacological ovulation induction. Ovarian drilling is a procedure in which a laser fiber or electro-surgical needle punctures the ovary four to ten times. Side-effects are rare and often related to surgery itself. Pharmacological strategies include administration of metformin and insulin-sensitizing agents, clomiphene citrate (CC), gonadotropins and aromatase inhibitors. Metformin appears valuable in increasing ovulation rate, menstrual cyclicity and pregnancy rate. CC is an oral estrogen antagonist that raises circulating concentrations of follicle-stimulating hormone (FSH) and induces follicular growth in most women with PCOS and anovulation. Failure to respond is associated with high body mass index and high androgen levels. Aromatase inhibitors mimic the central reduction of negative feedback through which CC works. Ovulation induction with recombinant FSH has proved successful, but treatment requires skill and experience to avoid multiple pregnancies and ovarian hyperstimulation syndrome. The hypothetical deleterious effects of the high luteinizing hormone concentrations observed in PCOS patients seem to be related to the concomitant hyperinsulinemia (and/or insulin resistance). A thorough understanding of the syndrome and a careful assessment of each patient are the mainstays for choosing an appropriate treatment regimen.

Keywords: Polycystic ovary syndrome, ovarian drilling, diet, metformin, clomifene citrate, gonadotropin, aromatase inhibitors

Introduction

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies in women, affecting 5 to 10% of women of fertile age. This syndrome not only interferes with reproduction but is in many ways a systemic disease [1-4]. Women with PCOS present at least two of the following features: polycystic ovaries, hyperandrogenism and anovulation. Because of the hormonal profile, women with this syndrome may also complain about abnormal bleeding, infertility, obesity, excess hair growth, hair loss and acne.

The pathogenesis of PCOS is poorly understood, but the primary defect may be insulin resistance leading to hyperinsulinemia. More precisely, although the insulin regulatory molecules on theca cells are responsive to insulin, those in the muscle and liver are resistant. In the ovary, the cardinal feature is functional hyperandrogenism. Circulating concentrations of insulin and luteinizing hormone (LH) are generally high. The theca cells, which envelop the follicle and produce androgens for conversion to estrogens, are over-responsive to this stimulation. They increase in size and overproduce androgens. The rise in LH levels is thought to be caused by the relatively high and unchanging concentrations of estrogens that may alter the feedback on the hypothalamic-pituitary axis. The high levels of androgens, estrogens, insulin and LH combined lead to the classic PCOS presentation of hirsutism, anovulation, dysfunctional bleeding and altered glucose metabolism.

Interest in PCOS has increased recently with the discovery that this syndrome involves far more than the reproductive system. PCOS is now recognized as a metabolic syndrome that may include hyperinsulinemia, hyperlipidemia, diabetes mellitus and possibly vulnerability to heart diseases, as well as the more conventionally recognized increase in androgen levels, cosmetic problems, anovulation, infertility, endometrial cancer and obesity [5,6].

Some authors have recently suggested that the condition may begin during fetal life, with either intrauterine growth retardation or post-term birth. Researchers have claimed that these children are more prone to hyperinsulinism, premature pubarche and signs of PCOS early in reproductive life [4,7]. Although the mechanisms interlinking premature pubarche, hyperinsulinism and ovarian hyperandrogenism remain unknown, this triad may result, at least in part, from a common early origin rather than from a direct relationship later on in life [8]. Among girls with precocious pubarche (defined as the appearance of pubic hair before 8 years of age), those with low birth weight (LBW) are, even if non-obese, at risk for progression to PCOS including hyperinsulinemia, hyperandrogenemia, dyslipidemia, dysadipocytokinemia and central fat excess [9].

Another study group investigated 27 girls with premature pubarche by ultrasonographic and color Doppler analyses to determine the incidence of polycystic ovaries (PCO), to assess their evolution longitudinally, and to search for any hormonal correlation. They found among girls with premature pubarche that the prevalence of PCO was 41%; advanced skeletal maturation, tall stature and increased hair distribution were constant in these patients. They concluded that girls with premature pubarche frequently present PCO; this condition progressively evolves into PCOS [1O].

Recently, Ong and colleagues examined the influence of birth weight and early postnatal weight gain on overnight fasting adrenal androgen and cortisol levels in 770 children aged 8 years from a large normal UK birth cohort. They found that adrenal androgen levels were highest in small infants who gained weight rapidly during early childhood. Based on these considerations they suggested that greater adrenal androgen secretion could be one link between early growth retardation and risk for adult diseases, possibly by enhancing insulin resistance and central fat deposition [11].

The hyperinsulinemia and dyslipidemia are detectable before and during pubertal development, and are commonly accompanied by low serum levels of insulin-like growth factor binding-protein 1 (IGFBP- I) and sex hormone-binding globulin (SHBG), and by an increased prevalence of anovulation from late adolescence onwards, even without any clinical signs of androgen excess. In girls, premature pubarche, hyperinsulinism, low IGFBP-I, dyslipidemia, anovulation and hyperandrogenism have been related to reduced fetal growth, with a hypothetical prenatal origin of this heterogeneous syndrome [12].

Early metformin therapy seems to prevent progression from precocious pubarche to PCOS in the high-risk group of formerly LBW girls. This confirms the key role of hyperinsulinemic insulin resistance in the ontogeny of PCOS. Furthermore, normalization of body composition, lipid profiles and growth hormone secretion could reduce long-term cardiovascular risk [9]. Unfortunately, in adolescents, the normalizing effects of metformin are reversed as soon as metformin therapy is discontinued [13].

The criteria used for the diagnosis and definition of PCOS are as heterogeneous as the pathology itself. There is an ongoing debate about the blood tests needed, if any. In PCOS women we find hyperactivity of the pituitary axis (higher LH pulses), overproduction of ovarian (androstenedione, testosterone) and adrenal (dehydroepiandrosterone sulfate) androgens, and also higher androgenic bioactivity related to lower SHBG and higher P450cl7 (17a- hydroxylase17,20-lyase) activity. Each one of these hormonal dysfunctions could be slight and not so valuable if considered alone.

Diagnosis of PCOS requires exclusion of lateonset congenital adrenal hyperplasia (measurement of 17-hydroxyprogesterone), thyroid abnormality (thyroid-stimulating hormone), hyperprolactinemia (prolactin) and Cushing's syndrome, but investigations must be prompted only in the presence of specific symptomatology. Measurement of testosterone (total or adjusted for SHBG) is helpful to show hyperandrogenemia and to rule out an androgensecreting tumor.

Because PCOS is now considered a metabolic syndrome it is suggested that patients have a thorough clinical evaluation. It is essential to exclude glucose intolerance. Insulin measurement alone has limited value; its interpretation may not be accurate in obese patients. Some investigators have recommended calculating an index of insulin resistance from glucose and insulin levels (e.g. the homeostasis model assessment (HOMA) or quantitative insulin sensitivity check index (QUICKI)) [14].

The incidence of obesity in women with PCOS varies between countries and ethnic groups. In the USA about 50% of women with PCOS are overweight or obese, but this prevalence differs little from that in the general community. In other countries, PCOS appears to be associated with obesity, but at a lower rate than in the USA. Obesity tends to be central (abdominal) in its distribution and even lean women with PCOS may have a fat distribution favoring central omental and visceral fat. An epidemiological study in the UK that followed up women with a histological diagnosis of PCOS after wedge resection of the ovaries found clear evidence of an increase in the rate of diabetes [15]. This confirmed the results of many other studies from the USA and Europe. In obese women with PCOS, progression from normal glucose function to impaired glucose tolerance or diabetes mellitus is more rapid than in women without PCOS [16]. Insulin resistance is independently re\lated to PCOS, as normal-weight PCOS women show a degree of hyperinsulinemia and impaired glucose disposal after meals and during glucose tolerance tests (oral or intravenous) [17]. It is uncertain whether this insulin resistance results from a specific genetic post-receptor defect, such as a defect in serine phosphorylation [18], or whether it is comparable to the problem seen in type 2 diabetes mellitus.

About 25 years ago most women with PCOS were found to be hyperinsulinemic and to have a glucose metabolism that was resistant to the stimulatory effects of insulin [19]. Insulin resistance in PCOS is not due primarily to obesity (as lean PCOS women can also be insulin-resistant) or to hyperandrogenism [20] (as androgen blockade reduces insulin resistance by only 10-15%) [21]. However determined, insulin resistance leads to hyperinsulinemia as pancreatic insulin secretion rises to maintain normoglycemia. Hyperinsulinemia can then stimulate lipid storage, altered lipoprotein and cholesterol metabolism and (possibly) altered steroid hormone metabolism. Hyperinsulinemia increases ovarian androgen production by stimulating an ovarian enzyme complex, cytochrome P450cl7, either directly and/or by stimulating pituitary LH secretion [22] (Figure 1). Moreover, in the past decade, studies have shown that women with PCOS have a high prevalence of hyperlipidemia [23-25], hypertension [26] and progression to type 2 diabetes mellitus [27], similar to the features of the so-called 'metabolic syndrome' or 'syndrome X'.

The advent of ultrasonographic examination of the ovaries has provided the biggest single contribution to the diagnosis of PCOS, having a high concordance rate with laparoscopy and histological examination. In fact, the assessment of ovarian morphology by transvaginal ultrasound and Doppler flow analysis of both intra- ovarian and uterine arteries seems to provide an insight into the pathological state and the degree of progression of the disease, and may be useful in the prevention and management of ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation [28].

Figure 1. Pathways to insulin resistance and polycystic ovary syndrome (PCOS).

At a recent joint American Society for Reproductive Medicine/ European Society for Human Reproduction & Embryology consensus meeting, a refined definition of PCOS was agreed, encompassing a description of the morphology of the polycystic ovary. According to the available literature, to fulfill criteria with sufficient specificity and sensitivity to define the PCO, patients should have at least one of the following: either 12 or more follicles measuring 2-9 mm in diameter, or increased ovarian volume (> 10cm^sup 3^). If there is a follicle > 10mm in diameter, the scan should be repeated at a time of ovarian quiescence in order to calculate volume and area. The presence of a single PCO is sufficient for the diagnosis. The distribution of follicles and a description of the stroma are not required. Increased stromal echogenicity and/or stromal volume are specific to PCO, but it has been shown that the measurement of ovarian volume (or area) is a good surrogate for the quantification of stroma in clinical practice. A woman having PCO in the absence of an ovulation disorder or hyperandrogenism, the so-called 'asymptomatic PCO', should not be considered as having PCOS. Three- dimensional and Doppler ultrasound studies may be useful research tools but are not required in the definition of PCO [29].

In a recent study of patients undergoing in vitro fertilization (IVF) cycles, Jarvela and co-authors showed that ovarian vascularization per follicle after pituitary suppression was lower in PCO patients. During ovarian stimulation, follicles in PCOS required a lesser amount of follicle-stimulating hormone (FSH) to acquire the same level of vascularization as the follicles in normal ovaries. In addition, they found that human chorionic gonadotropin (hCG) induced an increase in follicular vascularization in both the normal and polycystic ovary. The follicle count correlated with the total vascularized volume in the ovaries throughout the IVF cycle. They concluded that follicles in PCOS seem to be less vascularized than the follicles in normal ovaries after treatment with gonadotropin-releasing hormone (Gn-RH) but not after gonadotropin stimulation. It is possible that restricted blood supply to the follicles in PCO might be associated with the observed follicular arrest [30].

PCOS is frequently associated with infertility generally related to lack of ovulation because of a failure of the follicles to develop beyond 10mm in diameter. Most cycles are anovulatory, and induction of ovulation is needed. The choice of treatment depends on the patient's age and the presence of other infertility factors.

Treatment for women with PCOS must be individualized under two main categories: obese or non-obese, with or without insulin resistance. Many approaches have been proposed to restore ovulation, with the most frequently adopted therapies being ovarian drilling and pharmacological ovulation induction.

Therapeutic approaches

Surgery

The surgical approach to solve chronic anovulation in PCOS women consists of ovarian wedge resection, laparoscopic ovarian drilling (LOD) and vaginal ovarian drilling.

Ovarian wedge resection was the first surgical treatment proposed by Stein and Leventhal for ovulation induction [31]. This procedure was largely abandoned because of the greater risk of postsurgical formation of adhesions [32].

To reduce the invasiveness of the therapy, Gjoannaess in 1984 described a laparoscopic approach for ovarian drilling (LOD) with a unipolar electrode [33]. LOD at present may be performed by electrocoagulation or laser. Under general anesthesia, with three abdominal ports, one can produce multiple holes on the ovarian surface [34,35]. Several investigators have shown that there is no statistically significant difference in ovulation rates following LOD with electrocoagulation or laser (83% vs. 77.5%; odds ratio (OR) = 1.4, 95% confidence interval (CI) 0.9-2.1), although there is a significantly higher cumulative pregnancy rate at 12 months after surgery (65% vs. 54.5%; OR= 1.5, 95% CI 1.1-2.1) [33,35-38].

The mechanism of action is still not clear; however, LOD is associated with a decrease in androgen levels and changes in gonadotropin secretion and estrogen levels after the procedure [36]. There are many theories to explain why the laparoscopic destruction of androgen-producing ovarian stroma may prove beneficial in PCOS patients. First, the hypothalamic-pituitary-ovarian axis may be released from negative feedback owing to a decrease in substrate available for peripheral aromatization to estrogens, with an increase in FSH secretion and, consequently, follicular maturation and ovulation. This phenomenon may be enhanced by a decrease in inhibin levels. second, a decrease in intra-ovarian androgens also positively affects follicular maturation and ovulation. Finally, thermal injury of the ovary produces a number of growth factors, such as insulin-like growth factor-I, which sensitize the ovary to circulating FSH, resulting in stimulation of follicular growth and maturation [36,39-41].

This treatment determines a marked lowering of male hormones within days and is often performed in women who have PCOS. With this technique we can obtain restoration of hormonal profile (FSH, LH, LH/ FSH ratio, testosterone, Ferriman-Gallwey score), high prevalence of monofollicular ovulation, low rate of multiple pregnancy and exclusion of OHSS [42].

Many women who fail to ovulate with clomiphene citrate (CC) or metformin therapy will respond when these medications are administered after ovarian drilling. Side-effects are rare, but include adhesion formation or ovarian failure if there are complications during the procedure, no modification in glucose intolerance and insulin resistance, pelvic adhesions and loss of valuable ovarian tissue [42].

Reported adhesion formation rates following LOD range from zero to 100%. Therefore, surgical induction of ovulation may be useful only in selected cases: women with PCOS resistant to CC for whom gonadotropin therapy is unsuccessful or unavailable. There is no role for bilateral ovarian wedge resection in the treatment of anovulatory women with PCOS, as it is associated with low pregnancy rates due to an unacceptable incidence of peri-adnexal adhesion formation [43].

In 1991 Mio and associates showed that ultrasound-guided follicular aspiration may be an alternative surgical method for treating anovulatory patients with PCO; they observed spontaneous ovulation in PCOS women after transvaginal ultrasound-guided follicular aspiration [44]. De Geyter and co-workers in 1996 evaluated the outcome of ovulation induction in patients in whom supernumerary ovarian follicles were aspirated transvaginally, compared with the outcome in patients in whom this intervention was not necessary. They concluded that transvaginal aspiration does not affect ovulation and pregnancy rates in ovulation induction and intrauterine insemination [45].

More recently Ferraretti and colleagues demonstrated the effectiveness of a vaginal approach for ovarian parenchyma reduction in PCOS patients. They selected 11 women, out of 823 PCOS women undergoing assisted reproductive technologies (ART), based on poor response in at least two previous IVF cycles using Gn-RH agonist downregulation protocols. Before the ovarian stimulation the patients underwent transvaginal ovarian drilling (TVOD) under anesthesia with Propofol, using a 17-gauge, 35 cm-long needle connected to a continuous vacuum pressure. After TVOD all patients were asked to enter a new IVF cycle as soon as possible. No complications occurred in any patient. They summarize that, even if the number of cases is too small to draw any conclusions, TVOD is effective in improving ART results in di\fficult-to-treat patients with PCOS, and it is less invasive and less expensive than laparoscopic ovarian diathermy [46].

Pharmacological approaches

The cause of infertility in patients with PCOS is generally lack of ovulation because of a failure of the follicles to develop beyond 10mm. Most cycles are anovulatory, and induction of ovulation is essential. Available pharmacological strategies comprise metformin and insulin-sensitizing agents, CC, gonadotropins and aromatase inhibitors.

Metformin and insulin-sensitizing agents. In a study of women with PCOS performed about 25 years ago, most were found to be hyperinsulinemic and to have a glucose metabolism that was resistant to the stimulatory effects of insulin [19]. Insulin resistance is aggravated by physical inactivity, upper abdominal obesity, hyperandrogenism, pregnancy, the aging process and by medications such as thiazide diuretics, corticosteroids and certain hormonal steroid preparations.

Insulin resistance in PCOS is not due primarily to obesity, as lean PCOS women are insulin-resistant, or to hyperandrogenism [20], as androgen blockade reduces insulin resistance by only 10-15% [21]. Insulin resistance leads to hyperinsulinemia as pancreatic insulin secretion rises to maintain normoglycemia. Hyperinsulinemia can then stimulate lipid storage, alter lipoprotein and cholesterol metabolism and, possibly, alter steroid hormone metabolism. Hyperinsulinemia increases ovarian androgen production [22] by stimulating cytochrome P450cl7a, either directly and/or by stimulating pituitary LH secretion.

Insulin resistance is independently related to PCOS, with PCOS women of normal weight showing a degree of hyperinsulinemia and impaired glucose disposal after meals and during glucose tolerance tests (oral or intravenous) [17]. It is uncertain whether this insulin resistance results from a specific genetic post-receptor defect, such as a defect in serine phosphorylation [18], or whether it is comparable to the problem seen in type 2 diabetes mellitus.

Several studies have shown that weight loss can lead to resumption of ovulation within weeks [47,48]. Clark and co- investigators demonstrated that even a 5% reduction in body mass restores ovulation and fertility. These authors devised a program of exercise and sensible eating that has become a model across the world for treating PCOS [49,5O]. Attempts to reduce weight, increase exercise and stop smoking will fail if the woman with PCOS is not educated about the long-term adverse health implications of this condition. Too often these women are told only about the cosmetic nuisances of hirsutism or acne. However, while lifestyle changes are difficult to maintain, women seeking a pregnancy are highly motivated, making this a first-line intervention in overweight women with PCOS [51,52]. Longer-term changes in weight are more difficult to maintain. Obesity should be treated with a structured diet and exercise program [49]. Simply telling a patient to 'lose weight' or 'eat less' is unlikely to result in a significant reduction in weight, judging from experience in the management of type 2 diabetes. Consultation with dieticians working in type 2 diabetes or commercial weight-reduction programs may be useful in refractory obesity.

For women with very high body mass index (BMI) or not able to lose weight, use of metformin appears valuable in increasing ovulation rate, menstrual cyclicity and pregnancy rate. A recent consensus statement from the Endocrine Society of Australia indicated its use in women trying to become pregnant. There are many studies about the use of metformin in ovulation induction, especially comparing the efficacy of the biguanide versus CC, gonadotropin or surgical therapy.

In 2001 Vandermolen and associates carried out a randomized, double-blind, placebo-controlled trial demonstrating that, in anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate compared with CC treatment. Their findings suggest that metformin restores responsiveness to CC in many obese women with PCOS who remain anovulatory despite CC treatment, with metformin treatment increasing the rates of ovulation and pregnancy in these women [53]. A year later, Kocak and colleagues confirmed that significant reductions in serum androgens, LH and stimulated insulin levels, and higher ovulation and pregnancy rates may be expected in metformin- treated cycles in women with PCOS with CC resistance. They concluded that metformin seems to initiate orderly follicular growth when ovulation is induced with CC in patients with PCOS, suggesting metformin as a reasonable therapeutic option before or after CC treatment in such women [54].

The same year, at Ankara University, Yarali and co-workers carried out a prospective randomized trial to evaluate the impact of metformin on ovarian response when co-administered with recombinant FSH (r-FSH) using the low-dose step-up protocol in CC-resistant PCOS patients with normal glucose tolerance. They found that metformin may restore ovulation with no improvement in insulin resistance in CC-resistant PCOS patients with normal glucose tolerance, but has no significant effect on ovarian response during treatment with r-FSH [55]. However, more recently, Palomba and co-workers showed that in insulin-resistant women with PCOS, metformin pretreatment and co- administration of human pituitary FSH increases monoovulatory cycles [56].

A randomized, controlled trial conducted to compare the efficacy of sequential treatment with metformin and CC with conventional gonadotropins showed that sequential treatment is an effective and safe option for CC-resistant women with PCOS [57].

On the contrary, in 2002, a randomized, placebo-controlled, double-blind crossover study of 3 months of metformin (1500 mg/day)/ placebo, followed by 3 months of metformin/placebo together with CC (50-lOOmg for 5 days) for three cycles in CC-resistant women with PCOS suggested that caution needs to be applied when considering the value of metformin in women with PCOS. The authors did not find beneficial effects of metformin therapy in terms of androgens levels, insulin resistance, spontaneous ovulation, CC response and pregnancy rate [58]; in fact, literature data sustain that weight reduction per se is beneficial in women with PCOS [47,58,59]. The authors concluded that metformin may be beneficial in a subset, but by no means all patients with PCOS [58].

In 2003 a prospective study of 161 infertile, CC-resistant women with PCOS showed that such patients can be treated effectively by either metformin or LOD. Menstrual cycle pattern and the rates of ovulation and pregnancy are improved significantly, due most probably to the significant decrease in the levels of androgens and LH [60].

A meta-analysis with a systematic computerized literature search was done in 2004 showing that metformin is effective for ovulation induction and cycle regulation in this group of patients. Metformin plus CC appears to be very effective for the achievement of pregnancy compared with CC alone. No randomized controlled trial has directly compared metformin with CC and the need for such a trial remains [61].

Comparing metformin use with surgery, recent literature data confirm that LOD and metformin administration are similarly effective in inducing regular ovulatory cycles in a high percentage of anovulatory PCOS women [56,6O]. Moreover, the Palomba data show a significant difference between groups in pregnancy rate, with best results in the metformin group. Either LOD or metformin administration is effective in inducing ovulation in CC-resistant women with PCOS. A significant advantage in metformin administration seems to be related to a major improvement in pregnancy, abortion and livebirth rates. In addition, metformin is less expensive than LOD and it does not carry the risks of laparoscopy and general anesthesia [56].

In up to 20% of women, metformin causes side-effects which may include abdominal discomfort, cramps, diarrhea and nausea. The side- effects may be severe enough to make the woman want to stop metformin treatment, but can be minimized by taking metformin with a meal and starting with a low dose. It may be wise to begin with one 500 mg dose daily for the first week and increase to 500 mg twice daily during the second week. If gastrointestinal side-effects are mild after the second week, the dose of metformin may be increased to 850 mg twice daily. Patients with reduced renal function (creatinine > 1.5 or creatinine clearance <60%) are at a higher risk for a rare side-effect of metformin therapy called lactic acidosis, and the drug should be given cautiously, if at all, to such patients. Patients taking metformin should notify their physician and discontinue the medication: 48 h before surgery, 48 h before an intravenous pyelogram or other X-ray studies where an intravenous dye is administered, and in any case of shortness of breath, severe muscle weakness or chest pain, or abuse of alcohol.

The new insulin-sensitizing agents, the 'glitazones' - troglitazone (now banned by the US Food and Drug Administration because 35 patients out of approximately 1.5 million either died or required liver transplant), rosiglitazone and pioglitazone - have been shown to be very effective for ovulation induction, but are not approved by the Pharmaceutical Benefits Scheme for PCOS. They enhance the ability of smooth muscle to metabolize sugar, thereby reducing insulin resistance.

A randomized, controlled, double-blind trial was conducted to evaluate the effects of metformin and rosiglitazone, alone and in combination, in 100 non-obese PCOS women with normal indices of insulin sensitivity. Insulin-sensitizing drugs improved ovulation and decreased circulating testosterone. Metformin was more effective than rosiglitazone in improving ovulation, systolic blood pressure, \serum insulin levels and insulin sensitivity indices, and the addition of rosiglitazone to metformin did not add any benefit beyond that of metformin alone. However, these observations may be specific to the subset of non-obese PCOS women without clinically apparent insulin resistance. In conclusion, insulin-sensitizing drugs are useful in the treatment of non-obese women with PCOS who have normal clinical indices of insulin sensitivity [62].

However, there is great concern about the effects on the fetus of these drugs compared with metformin, and they should not be used by women trying to become pregnant. Women with PCOS have an increased prevalence of miscarriage, both after spontaneous and induced ovulation [63-66]. Hyper secretion of LH, hyperandrogenemia and hyperinsulinemia have all been investigated as possible causes of PCOS. It is likely that these factors are interlinked and, together, might result in disordered ovarian and endometrial function [67- 7O]. Other possible abnormalities have been postulated as contributing factors in the reproductive failure. These include decreased plasminogen activator inhibitor activity, endothelial dysfunction and obesity [71,72], conditions that frequently coexist in PCOS patients.

While safety during pregnancy has not yet been established, three patients who continued metformin during their entire pregnancy and one who remained on glitazone delivered normal babies. There are no reports of abnormal babies in women who conceived using metformin and all resulting babies were normal. Metformin is a category B medication. This means that insufficient human data are available but there are no credible animal data suggesting a teratogenic risk.

Although, to the best of our present knowledge, the risk of birth defects is small, it must be noted that maternal diabetes has been associated with an increased risk of birth defects and the underlying elevated insulin levels may lead to birth defects if not corrected. While the most prudent policy may be to avoid the use of these medications during pregnancy until more data on pregnancy outcome are available, the risk of miscarriage may be reduced by continuing metformin during the first trimester of pregnancy.

Clomiphene citrate. CC is an oral estrogen antagonist that raises circulating concentrations of FSH and induces follicular growth in most women with PCOS and anovulation. CC has always been the first- line therapy for these cases for the last 40 years. It is a simple, cheap treatment, almost devoid of sideeffects, which yields a single live birth in approximately 25% of starters [73].

The initial regimen is 25-50mg per day for 5 days. This treatment can be monitored by estrogen levels, follicular ultrasound examination and luteal progesterone level. Failure of response is associated with high BMI and high androgen levels. The gap between ovulation and pregnancy rates has also been attributed to its antiestrogen effects, and high LH and androgen concentrations. Recently, Jain and Kuo evaluated rates of spontaneous abortion, ectopic gestation, congenital malformations and stillbirth in two groups of patients treated with 50-100 or 150-250 mg CC/day. A dose of 150-250 mg/ day did not appear to increase adverse pregnancy outcomes [74].

A trial of a new regimen with CC administration to reduce the antiestrogenic effects on reproductive end organs showed that starting CC on the first day of the cycle for 3 days would lead to higher implantation rates compared with the classical 5-day CC therapy [75].

None of the other possible treatments (metformin, aromatase inhibitors and low-dose FSH) has been proved, as yet, to be a feasible replacement for CC as first-line treatment for ovulation induction in PCOS patients [76].

On the contrary, in a prospective, parallel, randomized, double- blind, double-dummy controlled clinical trial comparing CC and metformin as the first-line treatment for ovulation induction in nonobese PCOS anovulatory women, other authors showed that 6-month metformin administration is significantly more effective than six- cycle CC treatment in improving fertility in this patient group [77]. Metformin has been shown effective for ovulation induction and cycle regulation in PCOS patients. Metformin plus CC appears to be very effective for achievement of pregnancy compared with CC alone [61].

A randomized trial of CC versus low-dose r-FSH as first-line therapy for ovulation induction in women with PCOS suggested that the latter might be an effective alternative to CC in first-line treatment for anovulatory PCOS patients [78].

For CC-resistant PCOS women, metformin may be included in a stepwise approach before a surgical approach. LOD with electrocautery is superior to laser drilling and gonadotropin therapy [42].

Gonadotropins. Ovulation induction with r-FSH has proved successful, but demands skill and experience to avoid multiple pregnancies and OHSS.

In routine protocols of ART, patients start on low-dose r-FSH administered subcutaneously. Monitoring of ovarian response involves ultrasound examination associated with estradiol measurement. hCG is given when one follicle reaches 16-20 mm in size. More than two follicles of an appropriate size result in a risk of multiple pregnancies. Multiple gonadotrophin cycles may be required to achieve pregnancy, but this approach is preferable before more invasive procedures, such as IVF.

Acceptable cumulative conception rates have been achieved using conventional step-up treatment with gonadotropins. However, because of the peculiarly high sensitivity of PCO to gonadotropin stimulation, this form of treatment, employing incremental dose rises of 75 IU every 5-7 days, characteristically induces multiple follicular development, resulting in a high frequency of OHSS [78]. In fact, for ovulation induction in women with PCOS the problem of achieving the desired monofollicular ovulation is particularly difficult due to this extreme sensitivity of the PCO to gonadotropic stimulation. The high sensitivity is probably related to the fact that they contain twice the number of available FSH-sensitive antral follicles in their cohort than the normal ovary [79].

The chronic low-dose regimen of FSH was designed to reduce the rate of complication due to the development of multiple follicles [8O]. The principle of this protocol is to employ a low starting dose for 14 days and then use small incremental dose rises, when necessary, at intervals not shorter than 7 days, until follicular development is initiated [81,82]. This kind of stimulation is continued until the criteria for hCG administration are attained.

A low-dose, step-up gonadotropin therapy should be preferred to the now outdated conventional therapy for patients with PCOS, and the strong justification seems to be the almost complete elimination of OHSS and a multiple pregnancy rate of <6% [78,80,83,84].

The use of gonadotropins in IVF-embryo transfer or intracytoplasmic sperm injection protocols, because of the necessity of super-ovulation, could lead to high risk of OHSS. The standard protocol consists in suppression of the pituitary-ovary axis by Gn- RH agonists, with an initial stimulation of the pituitary and then a desensitization for the loss of pulsatile Gn-RH secretion. During the pituitary suppression (from 10 to 28-30 days after the administration) we give exogenous gonadotropins for ovarian stimulation.

A recent systematic review underlined that when PCO is present, the combined OR for OHSS is 6.8 (95% CI 4.9-9.6). The authors concluded that there is a significant and consistent relationship between PCO and OHSS [85]. When PCO are present before treatment with assisted reproduction, deliberate policies to moderate treatment appear justified.

Use of a Gn-RH agonist has not become a standard treatment for ovulation induction in PCOS despite the fact that literature data have shown an increased pregnancy rate and a lower miscarriage rate in women receiving combination treatment of agonist and gonadotropins when LH concentrations are high [86]. There are several reasons for this apparent anachronism. Co-treatment with Gn- RH agonist and low-dose gonadotropin therapy is more uncomfortable, longer, requires more gonadotropins to achieve ovulation, and has a greater prevalence of multiple follicle development and consequently more OHSS and multiple pregnancies. This combination therapy should be reserved for women with high serum concentrations of LH who have repeated premature luteinization, do not conceive on gonadotropin therapy alone or who have conceived and have had early miscarriages on more than one occasion [78].

More recently, Gn-RH antagonists (cetrorelix and ganirelix) have been used to achieve pituitary suppression. These drugs act with an antagonistic binding to Gn-RH hypothalamic receptors, without initial stimulation, and have a rapid mechanism of action. Many studies have been conducted to investigate the best dosage and protocol of administration and any interference with ART results. The authors conclude that Gn-RH antagonist use is associated with reduced gonadotropin doses, shorter period of treatment, lower incidence of OHSS, and less adverse effects on endometrium and follicles [87-9O]. Furthermore, Ragni and colleagues showed a favorable effect of Gn-RH antagonists in reducing the incidence of OHSS and the number of cancelled cycles in high responder patients. As a consequence, Gn-RH antagonist plus gonadotropin administration could also increase the percentage of oocyte retrievals and embryo transfers in this high-risk group of patients [91].

However, data from the literature seem to suggest that, in these patients, more than in normo-ovulating women, age is a crucial factor for good oocyte retrieval, fertilization, implantation and clinical pregnancy rates [92,93]. ART in its present form cannot make up for all births lost by the natural decline of fertility after ag\e 35 years [94].

Aromatase inhibitors. A group of new, highly selective aromatase inhibitors has been approved for use in postmenopausal women with breast cancer to suppress estrogen production. These aromatase inhibitors have relatively short half-life compared with CC and therefore would be eliminated from the body rapidly [95,96].

Some authors have proposed the use of aromatase inhibitors for inducing ovulation in PCOS women [97-99]. In 2001 Mitwally and Casper found that oral administration of letrozole is an effective, inexpensive method for stimulating follicular development. They concluded that aromatase inhibitors have potential as an alternative to, or even replacement for, CC as a first-line treatment for ovulation induction in anovulatory infertility and for augmentation of ovulation in ovulatory infertility patients [97]. More recently the same study group showed that the use of aromatase inhibitors in conjunction with FSH for controlled ovarian hyperstimulation for intrauterine insemination is associated with several advantages: reduced risk of severe OHSS and reduced risk of multiple pregnancy, as well as the significant reduction in the cost of treatment associated with high pregnancy rate [99].

A study comparing letrozole and anastrozole found that oral administration of aromatase inhibitors is effective for ovulation induction and conception in anovulatory CC-resistant women with PCOS, with a higher rate of success for letrozole than for anastrozole [98].

Aromatase inhibitors do not posses the adverse antiestrogenic effects of CC. In fact, endometrial thickness was not adversely affected by these treatments [98].

Despite all the evidence, in 2004 Kafali and associates showed that the administration of letrozole in rats can cause ovulatory failure and PCO, and speculated that substances that rather increase aromatase activity should be developed for treating PCOS [10O].

A randomized controlled trial showed the effectiveness of letrozole as a low-cost IVF protocol in women with poor ovarian response; no statistically significant differences were observed between the two groups in terms of total r-FSH dose administered, number of follicles, retrieved oocytes, transferred embryos, endometrial thickness and pregnancy rate. Only terminal estradiol levels were higher in the group treated with Gn-RH-agonist and r- FSH [101].

Letrozole has been proved effective also in a prospective randomized trial versus CC in women undergoing super-ovulation; the two drugs were associated with similar pregnancy rates, but the miscarriage rate was higher in the CC group [102].

In a cohort study published in 2005, Mitwally and co-authors evaluated the pregnancy outcome after the use of letrozole for ovarian stimulation, concluding that the favorable pregnancy outcome and low multiple gestation rate of aromatase inhibitors is encouraging for the development of these agents as first-line ovulation induction agents [103].

Further studies are necessary to find out the precise indications and dosage for the safe use of these emerging drugs.

Conclusions

The new concerns about PCOS women and the ongoing research about the genetic and prenatal implications of this condition suggest use of a multidisciplinary approach in these patients. The main goal is to increase the patients' chances of conceiving spontaneously once they enter the fertile age. The challenge of new-line therapies could be to change the destiny of young women with PCOS by acting as early as possible on the pathogenetic mechanisms that lead to this disorder.

Based on available data in the literature, we present a flow chart for ovulation induction in PCOS women (Figure 2). The first approach in a PCOS woman, with assessed bilateral tubal patency who seeks pregnancy, is to pay attention to weight loss and lifestyle modifications. These changes alone are sometimes able to restore cyclic menstruation and ovulation. In a young overweight woman (BMI ≤ 30 kg/m^sup 2^), one can adopt expectant management for at least 6 months before starting treatment.

Figure 2. Flow chart for the induction of ovulation.

The first line of medical treatment is still represented by CC; it is a simple-to-use drug with good compliance that needs little experience. We suggest trying 2 or 3 cycles with CC alone and, if no response/no pregnancy, add metformin (1500 mg/day) and try 3 more cycles with this protocol.

The next step is controlled ovarian hyperstimulation with r-FSH. The big problem with these drugs is the high risk of developing OHSS even with the lowest doses of gonadotropins. The avoidance of multiple pregnancies requires skill and experience.

After 4-6 cycles of controlled ovarian hyperstimulation it is advisable to resort to IVF techniques.

Because of the requirement for general anesthesia and the not so negligible surgical risk, LOD is suggested only in cases in which there is a concomitant reproductive disease, such as endometriosis, ovarian cysts or suspected tubal injury. The TVOD proposed by Ferraretti and colleagues is very appealing; however, larger studies are needed before this approach can be introduced routinely.

A thorough understanding of the syndrome and a careful assessment of each patient are the mainstays for choosing an appropriate treatment regimen. The multitude of treatment options available at present makes it possible successfully to treat most of the women who are subfertile due to PCOS.

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Source: Gynecological Endocrinology

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