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Abstract

Polycystic ovary syndrome is a common endocrinological problem in women of reproductive age. Polycystic ovary syndrome is a heterogenous disorder and patients may attend different clinics depending on the main complaint. The exact pathophysiology of polycystic ovary syndrome remains obscure, although there have been insights that have thrown light on this condition. Consensus on the definition of the syndrome has only been recently achieved. The management of polycystic ovary syndrome poses a challenge to the physician as responses to the different treatment regimes have proved to be inconsistent. Diet and lifestyle advice, restoration of menstrual cycle regularity, treatment of hyperandrogenism, treatment of infertility and prevention of long-term consequences form the basis of polycystic ovary syndrome management. This review aims to provide the reader with the latest evidence in the treatment of polycystic ovary syndrome, as well as focus on some of the controversies surrounding its management.

Keywords

insulin resistance insulin sensitizers ovulation induction polycystic ovary syndrome weight loss

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, with a prevalence of 5–15% [1]. Varying prevalence is quoted in the literature as a result of inconsistencies in diagnostic criteria. PCOS is a common presentation in the infertile population, amounting to approximately 20% of attendance in infertility clinics, and is the most common cause of anovulatory infertility (75–85%). The precise etiology of PCOS is still uncertain. Moreover, until recently there was no consensus regarding the definition of the syndrome. Not surprisingly, therefore, the definition of, and diagnostic criteria for, PCOS remain controversial [2,3]. It is now recognized that PCOS is a heterogenous condition with a collection of signs, symptoms and endocrine disturbances [4,5]. The common symptoms and signs include menstrual disturbances, presence of acne and hirsutism, obesity and infertility. Raised testosterone concentrations, elevated luteinizing hormone (LH), insulin resistance, lipid-profile changes and polycystic ovaries in ultrasound scans are biochemical and ultrasound features associated with the syndrome. The presentation is varied, with all or a combination of symptoms and signs forming a spectrum of a disorder that can change throughout the lifespan of the individual [1].

The guidelines that emerged from the Rotterdam consensus meeting in 2003 require the presence of two of the following three criteria for a diagnosis of PCOS [6]:

Chronic anovulation

Clinical and/or biochemical hyperandrogenism

Polycystic ovaries in ultrasound

In addition, other causes of hyperandrogenism and anovulation should be excluded.

There have been significant behavioral and lifestyle changes throughout the world over the last five decades. Consequently, the prevalence of obesity and the metabolic syndrome with accompanying insulin resistance and dyslipidemia has increased. PCOS is now recognized as belonging to the metabolic syndrome and therefore regarded as ‘a condition of our time’ [7].

The management of PCOS is based on the individual's need and primary symptoms. Management ranges from restoration of menstrual cyclicity, treatment of hyperandrogenism, treatment of infertility with ovulation induction or in vitro fertilization (IVF) and prevention of long-term consequences.

Weight loss & lifestyle modification

Obesity (body mass index [BMI] >30 kg/m²) is present in 50% of women with PCOS [8]. However, central obesity with increased visceral fat carries more metabolic risk than subcutaneous fat. Therefore waist circumference and waist:hip ratio, which are measures of central obesity, correlate significantly with increased insulin resistance. Kiddy and colleagues demonstrated that loss of more than 5% of body weight caused improvement in menstrual function in 82% of patients with oligomenorrhea compared with only 1% without weight loss [9]. This study also demonstrated a 40% reduction in hirsutism with more than 5% weight loss. The effect of weight loss on testosterone involves an increase in sex hormone-binding globulin (SHBG). With increased SHBG, the circulating level of free testosterone decreases, thus lowering the action of testosterone. A total of 40% of patients achieved spontaneous pregnancy in the weight-loss group. Moran and colleagues evaluated the effect of an energy-restricted diet (~1400 kcal/day) in 28 patients with a mean BMI of 37 kg/m² and noted that a 7.5% reduction in weight achieved a 15% chance of spontaneous pregnancy [10]. There is increasing evidence that weight loss and lifestyle modification improve menstrual cyclicity and ovulation [11,12]. Compared with normal-weight women with PCOS, those with obesity are characterized by a worsened hyperandrogenic and metabolic state, poorer menses and ovulatory performance and, ultimately, poorer pregnancy rates [13].

There are a multitude of diets that promise rapid weight loss. Choosing one over the other can be confusing. The principle of a diet in PCOS would logically target sugar, as insulin resistance is key in the pathophysiology. Carbohydrates with a low glycemic index are generally advocated. Starving is not recommended and timing of meals is also important as frequent small meals generate a lower mean serum insulin concentration compared with a single large meal. Obese women report difficulty in losing weight and maintaining weight loss. No difference in metabolic rate has been noted in PCOS and weight-matched controls [14]. Hypocalorifc diet, with or without increased physical activity, has been found to be efficacious. Most studies performed with hypocalorific diet clearly demonstrate improvement in the endocrine and metabolic profile of PCOS [15 –17].

The first step towards lifestyle modification is reduction of sedentary habits. Hu and colleagues demonstrated that a 2 h/day increment in television viewing was associated with a 23% increase in obesity [18]. The second step is increasing physical activity. It has been proven that moderate exercise is as effective as vigorous exercise in achieving weight loss [19,20]. The third step is to initiate an exercise regime and to comply with it.

Diet and exercise are the best measures to reduce body weight but difficult to achieve. It requires tremendous motivation. Education and support are paramount in any weight-loss program.

Weight-reducing drugs

Orlistat

Orlistat is a lipase inhibitor that leads to reduced absorption of fat from ingested food. The effect of orlistat in obesity associated with PCOS has been studied and a beneficial effect has been recorded [21]. In another study by Jayagopal and colleagues, orlistat has been found to achieve significant weight loss and reduction in total testosterone, probably secondary to weight loss [22]. The 2001 National Institute for Clinical Excellence (NICE) guidelines on the use of orlistat in obesity state that orlistat should only be used when the patient has lost at least 2.5 kg by diet and exercise in the month prior to their first prescription. BMI should be 28 kg/m² or more in the presence of other diseases such as diabetes mellitus or hypertension, or 30 kg/m² or more in the absence of another significant disease. Orlistat should be prescribed for 3 months initially and treatment is continued only if a 5% loss in body weight is demonstrated during treatment [201]. Continuation beyond 6 months is subject to loss of 10% of body weight. Treatment beyond 12 months is not recommended. As orlistat prevents the absorption of fat molecules, 30% of ingested fat is excreted in feces, which can lead to ‘fatty stools’. Patients may also experience urgency and increased frequency of defecation. As orlistat may interfere with the absorption of fat-soluble vitamins, supplementation may be required.

Sibutramine

Sibutramine is a centrally acting stimulant chemically related to amphetamine, meth-amphetamine and phentermine. Sibutramine acts by increasing serotonin and noradrenaline levels in the brain, enhancing feelings of fullness and satiety, and has been found to be effective in treatment of obesity in adolescents [23]. However, it raises blood pressure and is not suitable for anyone with a blood pressure of 140/90 mm Hg or above [24].

Oral contraceptives

Oral contraceptive pills have been the mainstay of treatment for menstrual irregularity for decades. Cyclically administered contraceptive pills will cause regularization of the menstrual cycle and also help in amelioration of hyperandrogenism. Oral contraceptives decrease gonadotropin secretion and increase SHBG production by the liver, reducing bioavailable testosterone by 40–60% [25]. However, oral contraceptives carry a risk of thromboembolism when continued over long periods. Moreover, they have a potentially detrimental effect on insulin sensitivity [26]. Combined pills can also worsen hypertrigyceridemia. The newer formulations may be more suitable in avoiding the adverse effects of earlier formulations (see below). Ethinyl estradiol and cyproterone acetate (CPA), which is an antiandrogen, would be appropriate when the presenting symptoms are oligomenorrhoea and acne or hirsutism. If cyclical menstruation is not desired or for those who cannot have estrogen (obesity, hyper-coagulable states, smokers aged >35 years), periodic progesterone to cause periodic endometrial shedding is an option. Amenorrhoeic women with PCOS should have a progesterone-induced bleed once every 3 months to prevent endometrial hyperplasia.

Oral contraceptives attenuate hyperandrogenic features via suppression of LH and increase secretion of SHBG, inhibition of 5-α reductase and androgen receptor binding, which results in reduction of plasma androgens [27]. Few clinical trials have compared the various estrogen–progestagen combinations available in the treatment of PCOS. However, oral contraceptives are not ideal for insulin-resistant patients who have a tendency to develop diabetes mellitus [28]. Several studies have recorded increases in insulin and glucose in response to oral glucose tolerance during treatment with the combined pill [29]. But this increase has not been observed in patients aged under 26 years [30]. Variations in insulin sensitivity have not been observed with low-dose estrogen–progestin combinations [31]. Estrogen–progestin combinations commonly used in PCOS are ethinyl estradiol with either CPA or drospirenone.

Cyproterone acetate

Ethinyl estradiol 35 μg and CPA 2 mg (marketed as Dianette®, Schering Pharmaceuticals) is a popular choice in PCOS with hyperandrogenic features. CPA is a potent progestagen and antiandrogen. CPA blocks the binding of dihydrotesteosterone (DHT) to its receptor, reduces 5-α reductase activity and impaires androgen synthesis [32]. A significant improvement in acne and seborrhea was observed in the 12th and 24th cycle of treatment while hirsutism, although improved, did not resolve after 60 cycles of treatment [32]. A high BMI is found to reduce the beneficial effects of the treatment [31].

Drospirenone

Drospirenone is a 17-α progestagen derived from spironolactone and contained in a 30 μg ethinyloestradiol preparation (marketed as Yasmin®, Schering Pharmaceuticals). The progestational efficacy of drospirenone is similar to that of natural progesterone, with mineralocorticoid and antiandrogen activities [33]. This preparation causes an increase in SHBG and has significant antiandrogenic activity, alleviating acne, seborrhea and moderate hirsutism. Yasmin demonstrated good cycle control and alleviation of acne in PCOS [34]. The beneficial effect was found to be most obvious after six cycles and then continue at a slower rate [34]. A significant increase in high-density lipoprotein (HDL) cholesterol serum concentrations were noted in women with PCOS treated with Yasmin. The efficacy of Yasmin has been found to be comparable with the combination containing CPA [35]. The disadvantages with oral contraceptive pills (estrogen–progestin combination) are the return of symptoms when treatment is suspended and no improvement in the metabolic aspect of PCOS.

The combination of estrogen and a progestin is probably most appropriate for young women with PCOS with moderate clinical symptoms of hyperandrogenism. Contraception is an added benefit.

Antiandrogen therapy

Spirolonolactone

Spironolactone is a diuretic that prevents DHT from binding with its receptor and suppresses 17-hydroxylase and 17–20-desmolase and 5-α reductase. Spironolactone is effective in reducing terminal hair growth [36]. Spironolactone may cause salt depletion and needs assessment of renal function. It may also cause polymenorrhoea as well as headaches, mood swings, fatigue, muscle cramps and reduced libido. Pregnancy should be avoided for at least 4 months after the use of spironolactone [37].

Finasteride

Finasteride is an inhibitor of 5-α reductase, particularly type 2-α reductase, and decreases DHT. Significant improvement is noted 6 months after treatment [38]. Finasteride is prescribed in doses of 5 mg or 2.5 mg daily. Low-dose finasteride (2.5 mg/day) has been found to be cost-effective and well-tolerated, without significant abnormal biochemical findings, and as effective as the higher dose [39]. In a prospective, randomized study, 38 women with idiopathic hirsutism or PCOS received finasteride 2.5 mg everyday or every 3 days. Intermittent low-dose administration of finasteride was found to be as effective as continuous administration in reducing hirsutism score and was accompanied by a lower incidence of side effects [40]. Pregnancy should be avoided whilst receiving treatment with finasteride.

Flutamide

Flutamide is an antiandrogen with no intrinsic hormonal activity. Flutamide inhibits the cellular uptake of testosterone and 5-α dihydrotestosterone. Significant reduction of hirsutism is achieved with no hormonal changes [41]. Flutamide may also reverse hyperinsulinaemia [42], but this is still under debate [43]. Flutamide eliminates the hypothalamic block exerted by androgens and restores the sensitivity of the gonadotropin-releasing hormone (GnRH) pulse to endogenous estrogen and progesterone [44]. It is one of the most potent antiandrogens available but has been associated with hepatic toxicity and therefore, while favored by some authors, is not a therapy that we would recommend in the management of PCOS.

Antiandrogens are potentially teratogenic and can cause feminization of a male fetus. Antiandrogens are best administered with oral contraceptives [45].

Mechanical methods of treating hirsutism

Mechanical methods to control hirsutism include shaving, epilation, waxing, depilatory creams, electrolysis and laser treatment. These are used in varying degrees and realistically form the mainstay of treatment of severe hirsutism. Shaving is most helpful among them, with the least side effects of folliculitis or skin irritation, which can occur with injudicious use of waxing or depilatory creams [46].

Electrolysis involves the use of galvanic current passed down through a needle into the hair follicle. Thermolysis uses alternating current passed through a needle into the hair follicle to cause thermal damage to the hair follicle. The third method uses a combination of galvanic current and thermolysis [47]. Though effective, electrolysis is not convenient for very large areas and needs to be combined with antiandrogens. The principle of laser treatment is to cause thermal damage to the hair follicle without risk of damage to adjacent tissue [48]. Type of laser used in treatment of hirsutism are red-light systems (694 nm ruby), infrared-light systems (755 nm alexandrite, 800 nm semiconductor diode, Nd: yag) and intense pulsed-light sources (590–1200 nm).

Vaniqa®

Eflorithine hydrochloride crème is marketed under the brand name of Vaniqa® (Shire Pharmaceuticals). Eflorithine inhibits ornithine decarboxylase, which is necessary for the production of polyamines involved in cell migration, proliferation and differentiation. Originally used for African sleeping sickness, hair loss was observed as a side effect and was used topically for retarding hair growth. Studies conducted for 24 weeks showed marked improvement in 32%, and 58% demonstrated some improvement [49]. Eflorithine has been found to be well tolerated with minor side effects such as stinging of skin and skin rashes. Systemic absorption of topical eflorithine is minimal but it is best avoided during pregnancy as it is an antimitotic and antidifferentiation agent.

Insulin sensitizers

The use of insulin-sensitizing agents in the treatment of PCOS is based on the theory that hyperinsulinaemia is key in the pathophysiology of PCOS. The first drug to be used was diazoxide, to suppress plasma insulin in women with PCOS [50]. Fasting and glucose-stimulated insulin levels were found to be markedly reduced. Total serum testosterone levels were also found to be significantly reduced. The biguanides phenformin and metformin have also been tried in PCOS. The use of phenformin fell into disrepute because of the incidence of lactic acidosis [51]. Metformin is safer because it does not bind to plasma proteins and is therefore rapidly eliminated through the kidneys [52]. Metformin lowers fasting serum insulin levels in obese nondiabetic individuals without producing hypoglycemia [53]

Metformin

The precise mechanism of action of metformin remains unknown. The following effects of metformin on glucose metabolism have been documented. Metformin has been shown to significantly reduce basal hepatic glucose production in subjects with Type 2 diabetes [54,55]. It inhibits hepatic glucose production by 9–30%. In isolated hepatocytes, therapeutic concentrations of metformin enhance the suppression of gluconeogenesis by insulin and reduce glucagon-stimulated gluconeogenesis [56].

Metformin increases insulin-stimulated glucose utilization (estimated by means of the hyperinsulinemic clamp) by up to 50% in subjects with Type 2 diabetes [57] or normoglycemic insulin resistance [58]. Metformin seems to facilitate the translocation of glucose transporters from intracellular sites to the plasma membrane, enhancing insulin-stimulated glucose transport into cells [59].

A report has indicated that metformin significantly reduces fasting insulin levels in non-diabetic subjects. After 12 months, 164 patients taking metformin showed a reduction in plasma insulin of approximately 36 pmol/l [60]. It has recently been shown that metformin enters the cell and directly stimulates the tyrosine kinase activity of the intracellular portion of the subunit of the insulin receptor [61].

Metformin is the most extensively investigated insulin sensitizer and the most clinically used in PCOS. Metformin decreases fasting and post-oral glucose load plasma insulin levels [62]. Metformin is found to reduce hyperandrogenism and restore normal secretion of LH [63,64]. Long-term administration of metformin is seen to achieve reduction in both free and bound testosterone [65]. The effect of metformin on hyperandrogenism in PCOS involves the direct inhibitory action on androgen secretion by ovarian thecal cells, inhibition of LH secretion and increased androgen binding secondary to the enhanced SHBG synthesis [66]. However, metformin, which evidently reduces free- and total-androgen content, produces only a slight impact on skin manifestations of hyperandrogenism [67,68]. Other observed effects of metformin on lipid metabolism are decreased levels of low-density lipoprotein (LDL) cholesterol and triglycerides, and elevation of HDL cholesterol [43]. It is important to note that many other studies have not been able to demonstrate the effectiveness of metformin in their study populations [69,70]. One of the largest randomized, controlled trials examining the effect of metformin found no beneficial effect independent of weight loss [12].

In the meta-analysis by Lord and colleagues, which included 13 controlled trials, metformin was found to significantly lower insulin levels [71]. The analysis also demonstrated a slight but significant decrease of LDL-cholesterol levels, with no effect on HDL cholesterol and total triglycerides. The discrepancy of results could be due to the difference in populations studied, mean BMI, level of insulin resistance and dosage. As of now, metformin is considered to be beneficial for some individuals, although clear algorithms for its use have not been elucidated, including who will benefit, when to start, dose and duration of therapy. Much more work is therefore required to research the appropriate use of metformin in the management of PCOS.

Troglitazone, pioglitazone & rosiglitazone

Troglitazone was the first oral thioglitazone approved for use in noninsulin-dependant diabetes mellitus. Most studies demonstrate that troglitazone improves insulin sensitivity without direct effects on insulin secretion and exerts beneficial effects on metabolic profile and reproductive function in PCOS [72,73]. Although troglitazone was found to be well tolerated, it was reported to cause mild anemia and neutropenia, which were reversible after drug discontinuation [74]. However, a review conducted in 2000 demonstrated significant hepatotoxicity of troglitazone in comparison with pioglitazone and rosiglitazone, and the US FDA has removed it from the market [75]. A significant amelioration of insulin sensitivity, secretion and clearance has been observed in hyperinsulinemic PCOS with pioglitazone [76]. The effect of pioglitazone seems to be selective and partially independent of insulin secretion. Similar findings have been observed with rosiglitazone [77]. Pioglitazone has been found to be as effective as metformin in obese women with PCOS in reducing fasting and 2 h glucose-driven insulin secretion [78].

D-chiro inositol contains phosphoglycan, which mediates the action of insulin. Therefore, replenishing d-chiro inositol can improve insulin sensitivity. This drug was first studied by Nestler and colleagues and the results have been extended by Iurno and colleagues, and Gerli and colleagues [79 –81]. Improved insulin action was observed, with ovulation in 86% of women [79].

Management of infertility

PCOS accounts for 80–90% of anovulatory infertility [82,83]. The mainstay of correction of anovulation lies with ovulation induction. The key to success is the attainment of a normal body weight, as those who are overweight have reduced spontaneous fertility, a reduction in response to ovulation-induction therapy and increased pregnancy problems such as congenital anomalies, miscarriage, gestational diabetes, pre-eclampsia, stillbirth and neonatal death.

Clomifene citrate

Clomifene citrate is the first choice in the management of anovulation in PCOS and has been in use since 1962. Clomifene citrate is an anti-estrogen that leads to greater than 50% increased secretion of follicle stimulating hormone (FSH) from the pituitary gland [84]. Clomifene is given at a dose of 50–150 mg daily for 5 days from day 2 to day 5 of a spontaneous or induced bleeding [85,84]. Studies with clomiphene citrate have shown an ovulation rate of 60–85% and a pregnancy rate of 30–40% [85 –88]. Miscarriage rates in the same studies have been reported to be between 13 and 25% [89]. Approximately 20–25% of patients are found to be clomifene resistant [90]. High basal LH levels are not conducive to conception and clomifene citrate stimulates both FSH and LH. An increased LH concentration immediately after administration of clomiphene citrate predicts an adverse pregnancy outcome. The antiestrogenic effect of clomifene citrate may suppress endometrial growth and secretion of cervical mucus. The cumulative conception rate continues to rise after 6 months of treatment with clomiphene citrate, reaching a plateau by treatment cycle 12 [91]. Therefore, anovulatory women responsive to clomiphene citrate should be treated for at least six cycles and not more than 12 cycles before proceeding to more complex or invasive methods of ovulation induction or IVF. A limit of 12 cycles of clomifene is recommended owing to a slight risk of ovarian cancer with prolonged use of clomifene citrate (in excess of 12 cycles) [92], although this association has not been consistently observed [93]. The risks of ovarian hyperstimulation and multiple pregnancy are minimized by conducting ovulation induction under ultrasound monitoring and canceling cycles with more than two follicles measuring more than 14 mm. As high LH is detrimental to good outcome, it is good practice to measure day 8 LH [91]. Prolonged use of clomifene has been linked to an increase risk of ovarian cancer. In a retrospective analysis of 12,193 patients a small risk was observed in some subgroups, which did not meet statistical significance [94].

Adjuvants to clomifene citrate are human chorionic gonadotropin (hCG) and metformin. hCG is administered at a time when the follicle measures 18–24 mm and helps timed intercourse or intrauterine insemination. However, it has been found not to add to conception rates when used routinely [95]. Lord's systematic analysis showed a benefit of using metformin in improving ovulation rates, however, two recent, large, randomized, controlled trials by Moll and colleagues, and Legro and colleagues demonstrated no benefit from the addition of metformin when compared with a placebo [96,97].

Gonadtropin therapy

FSH or human menopausal gonadotropin (hMG) is usually reserved for patients not responding to clomifene citrate, or those who persistently hypersecrete LH or experience antiestrogenic side effects of clomifene citrate. It has been found safe to start gonadotropins on a lower dose and the low-dose step-up protocol significantly reduces multiple pregnancy rates and avoids ovarian hyperstimulation syndrome (OHSS), while achieving good pregnancy rates [98]. Induction is started on a low dose and increased if no response is observed in 14 days. The dose that initiates follicular reduction is continued until the lead follicle is 17–18 mm. The conventional step-up protocol increases multiple pregnancy rates to 34% and OHSS to 4.6% [99]. The step-down protocol uses the normal ovulatory cycle as a template. A starting dose of approximately 150 IU of FSH or hMG is used and the dose reduced once follicular selection takes place [100]. The step-down protocol achieves 88% ovulation rates [100]. The amount of gonadotropin required and the duration of treatment are reduced in the step-down protocol [100]. However, a French multicenter study found the low-dose step-up protocol to be superior to the step-down protocol [101]. Strict criteria are followed to avoid the risk of OHSS and multiple pregnancies. Cancellation of cycles in the presence of more than seven follicles of more than 8 mm on day 8 prevents OHSS [102] and withholding administration of hCG if more than two follicles measuring more than 14 mm are present significantly reduces the risk of multiple pregnancy. As far as gonodotropin preparations are concerned, no difference has been noted in pregnancy or miscarriage rates between urinary FSH and hMG [103].

Gonadotropin hormone-releasing hormone agonists

The GnRH agonists are not popular ovulation-induction agents in PCOS. The use of GnRH suppresses LH and therefore may theoretically benefit patients with high baseline LH. Increased pregnancy rates have not been reported with the use of GnRH compared with hMG alone [103]. Furthermore, the concomitant use of GnRH is cumbersome and leads to multiple follicle development with increased risk of OHSS and multiple pregnancy.

Laparoscopic ovarian diathermy

Laparoscopic ovarian diathermy (LOD) frequently induces ovulation in patients with PCOS. Surgical ovarian wedge resection was the first established treatment for anovulatory PCOS patients but was largely abandoned due to the risk of postsurgical adhesions and the introduction of medical ovulation induction with clomifene and gonadotropins. Surgical therapy with laparoscopic ovarian ‘drilling’ may avoid or reduce the need for gonadotropins or may facilitate their use. There was no evidence of a difference in the live birth rate and miscarriage rate in women with clomiphene-resistant PCOS undergoing LOD compared with gonadotropin treatment. The reduction in multiple pregnancy rates in women undergoing LOD makes this option attractive [104]. LOD seems to be appropriate for patients with high baseline LH levels, as LH and testosterone levels are found to drop after LOD [105]. The mechanism by which ovarian function is restored remains largely unexplained. Monopolar diathermy electrocautery and lasers are commonly used to perform drilling of the ovaries. The greater the amount of damage to the ovarian surface the greater the risk of periovarian adhesions. The number of punctures in the ovary has not been standardized ranging from 4–8 points, for 5–6 s with 300–400 W [106]. However, owing to risk of ovarian destruction and periovarian adhesions, Amer's strategy of using 4 points/ovary for 4 s at 40 W seems reasonable and was reported to achieve pregnancy rates of 80% [107]. It has also been demonstrated that diathermy to one ovary is sufficient to achieve bilateral ovulation [108]. In the largest randomized, controlled trial to be performed to date, pregnancy rates with LOD were 50% lower than the use of FSH after 6 months/six cycles [109], thus LOD is best reserved for those who find it difficult to attend for the regular ultrasound monitoring that is required with FSH therapy.

Aromatase inhibitors

Aromatase inhibitors (AIs) suppress estrogen production and stimulate FSH secretion from the pituitary gland. The advantage of AIs (e.g., letrozole) over clomifene is the absence of antiestrogenic activity on target organs such as the endometrium and cervical mucus. Letrozole has been found to be effective in clomifene-resistant PCOS [110]. More data are awaited regarding the safety and efficacy of letrozole, which has recently been withdrawn from use because of a study reported at the American Society for Reproductive Medicine meeting in 2005, which reported low birthweight and some cardiac and locomotor abnormalities in a retrospective analysis of 150 births [111]. However, a comparison of 911 newborns conceived with either clomifene citrate or letrozole demonstrated no difference in the overall rates of major and minor congenital malformations. Moreover, congenital cardiac anomaly was less frequently observed in the letrozole group [112]. Preliminary evidence suggests that AIs have similar efficacy as clomifene citrate but a reduced side-effect profile. Although worldwide experience with AIs for ovulation induction is increasing, at present, definitive studies in the form of randomized, controlled trials comparing clomifene citrate with AIs are lacking [113]. Furthermore, they are off-license for the management of infertility.

In vitro fertilization

IVF is recommended when women with PCOS fail to conceive with ovulation induction and success rate with IVF in PCOS is comparable to tubal factors [114]. However, the risk of OHSS is considerably higher in PCOS. In a systematic review the combined odds ratio for OHSS in the presence of PCOS was found to be 6.8 (95% confidence interval: 4.9–9.6), demonstrating a consistent and significant relationship between PCOS and OHSS [115]. A meta-analysis comparing PCOS and control patients undergoing IVF demonstrated an increased cancellation rate, but more oocytes retrieved per retrieval and a lower fertilization rate in PCOS patients [116]. Short-term co-treatment with metformin for patients with PCOS undergoing IVF/intracytoplasmic sperm injection cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS [117]. In vitro maturation of oocytes is a potential strategy to minimize the risk of OHSS in PCOS [118]. The miscarriage rate, gestational age and birth weight at delivery, and obstetric complications of pregnancies conceived by in vitro maturation-embryo transfer in women with PCOS were found to be comparable with those of other women with PCOS being treated by conventional IVF-embryo transfer [119].

PCOS in adolescents

In adolescents the diagnosis of PCOS can be difficult. Some features, such as menstrual-cycle irregularities and presence of acne, are difficult to differentiate from symptoms of puberty. Moreover, transvaginal ultrasound examination is not appropriate in many cases and ultrasound features of PCOS may not be clearly visible in abdominal scans. The application of the Rotterdam criteria would therefore require family history, clinical examination, tests for hyperandrogenism and exclusion of other causes of hyperandrogenism such as Cushing's syndrome, congenital adrenal hyperplasia and adrenal tumours. Once diagnosis is established, therapeutic goals to be achieved are restoration of normal body weight in case of the overweight or obese, establishment of regularity of menstruation and alleviation of acne and hirsutism. In most cases lifestyle counseling and loss of weight if overweight is appropriate. Oral contraceptives are a good option when acne and hirsutism are the principal complaints [120]. Adolescents with isolated cycle irregularity may be placed on a cyclical progestin regimen to induce withdrawal bleeding [121]. In adolescents with PCOS, metformin and diet reduce weight, insulin, insulin resistance, cholesterol and triglycerides, and facilitates the resumption of regular menses [122]. It may be used alone or in combination with oral contraceptives.

Long-term consequences & follow up

Features of the metabolic syndrome, including obesity, insulin resistance and dyslipidemia, are common in women with PCOS. Therefore, ongoing surveillance is required to detect impaired glucose tolerance, dyslipidemia, endometrial hyperplasia and consequent complications. Women with PCOS and baseline impaired glucose tolerance test have a conversion risk of 6% to Type 2 diabetes over approximately 3 years, or 2% per year. In PCOS patients with normal glucose tolerance, a 16% conversion to impaired glucose tolerance has been observed per year [123]. Consequently, there is evidence to support periodic rescreening for diabetes in women with PCOS.

Cross-sectional studies have demonstrated a significant association between PCOS and ischemic heart disease [124,125]. Echocardiography, imaging of coronary and carotid arteries and assessments of both endothelial function and arterial stiffness have recently been employed to address this question. These studies have collectively demonstrated both structural and functional abnormalities of the cardiovascular system in PCOS [126]. Long-term longitudinal studies are awaited to confirm this association. An investigation into the long-term consequences, by Wild and colleagues, revealed the presence of risk factors for cardiovascular disease but no increase in morbidity or mortality compared with comparison groups [127,128]. However, the study documented an increased risk of endometrial cancer among women with PCOS. Elevated estrogen (without the opposing effects of progesterone in the absence of ovulation), hyperinsulinemia, elevated free insulinlike growth factor and androgens, and obesity are all likely to contribute to endometrial dysfunction [129]. Therefore, it is essential that oligomenorrhoeic and amenorrhoeic women shed their endometrium from time to time.

Future perspective

PCOS is a syndrome that impacts women both physically and psychosocially. PCOS has a negative impact on health-related quality of life even when compared with other serious health conditions [130]. Increased body weight and hirsutism causes poor body image and directly correlates with reduced quality of life and sexual satisfaction [131]. Effective and comprehensive management of PCOS should focus on issues of quality of life.

There is evidence for a genetic basis in PCOS based on familial clustering of cases. Steroidogenesis has been demonstrated to be upregulated in theca cells of ovaries in PCOS, suggesting that the genetic abnormality in PCOS affects signal transduction pathways controlling the expression of a family of genes [132]. Although a number of candidate genes have been proposed, the actual PCOS gene or genes have not been identified. Recent studies implicate a region near the insulin receptor gene at chromosome 19p13.3 [133]. More insight into the genetic basis of PCOS and familial inheritance will incorporate genetic counseling into the management of this condition.

Conclusion

The heterogeneity of PCOS and individual needs make the management of PCOS complicated. The appropriate approach should be multidirectional and holistic. The condition of PCOS is not confined to the realm of reproductive medicine, as patients will attend other clinics such as dermatology and endocrinology. The first step in therapy is the minimization of symptoms. Management needs to be individualized with due focus on comorbidities and risk factors. Fertility is obviously a key issue as the patients belong to the reproductive age group. In the absence of male factors for infertility, ovulation induction achieves good results. However, resistance to clomifene and erratic response to ovulation-induction regimes is not uncommon. An agreed definition and better understanding of the pathophysiology of PCOS has helped in standardizing treatment. Traditional therapies such as oral contraceptives and clomifene still form the backbone of treatment. However, new progestins and antiandrogens have improved effectiveness and compliance of oral contraceptives. However, PCOS continues to be a subject of debate. Long-term prospective data are required to confirm and examine the disease associations but, in the mean time, emphasis on weight maintenance and close follow-up is prudent.

Executive summary

The management of polycystic ovary syndrome (PCOS) is based on the individual's need and primary symptoms.

Weight loss & lifestyle modification

Diet and exercise are the best measures to reduce body weight but are difficult to achieve. It requires tremendous motivation. Education and support are paramount in any weight-loss program.

Hypocalorifc diet with or without increased physical activity has been found to be efficacious.

Weight-reducing drugs

Orlistat can be used in some cases to augment weight loss if the patient demonstrates some weight loss with diet and exercise.

Oral contraceptives

Oral contraceptives are the mainstay of treatment for menstrual irregularity, especially if contraception is required.

The combination of estrogen and a progestin is probably most appropriate for young women with PCOS with moderate clinical symptoms of hyperandrogenism.

Oral contraceptives containing cyproterone actetate are effective in the treatment of hirsutism and acne.

Antiandrogen therapy

Spironolactone, finasteride and flutemide are used with varying results to treat signs of hyperandrogenism.

Antiandrogens are potentially teratogenic and can cause feminization of a male fetus. Antiandrogens are best administered with oral contraceptives.

Insulin sensitisers

Insulin sensitizers such as metformin have no proven long-term benefit in the management of PCOS and no clear benefit in the management of anovulatory infertility.

Ovulation induction

Clomifene citrate is the first-line ovulation-inducing agent and has good pregnancy rates.

A total of 20–25% of patients are found to be clomifene resistant and need human menopausal gonadotropin or follicle-stimulating hormone for ovulation induction.

Follicle-stimulating hormone or human menopausal gonadotropin is usually reserved for patients not responding to clomifene citrate, or those who persistently hypersecrete luteinizing hormone or experience antiestrogenic side effects of clomifene citrate.

Long-term consequences & follow-up

Cross-sectional studies have demonstrated a significant association between PCOS and ischemic heart disease.

Future perspective

Quality of life issues and genetic basis of PCOS are subjects of focus.

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Management of Polycystic Ovary Syndrome

Abstract

Keywords

Weight loss & lifestyle modification

Weight-reducing drugs

Orlistat

Sibutramine

Oral contraceptives

Cyproterone acetate

Drospirenone

Antiandrogen therapy

Spirolonolactone

Finasteride

Flutamide

Mechanical methods of treating hirsutism

Vaniqa®

Insulin sensitizers

Metformin

Troglitazone, pioglitazone & rosiglitazone

Management of infertility

Clomifene citrate

Gonadtropin therapy

Gonadotropin hormone-releasing hormone agonists

Laparoscopic ovarian diathermy

Aromatase inhibitors

In vitro fertilization

PCOS in adolescents

Long-term consequences & follow up

Future perspective

Conclusion

References