Review

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Polycystic ovary syndrome: chemical pharmacotherapy Morena Luigia Rocca, Roberta Venturella, Rita Mocciaro†, Annalisa Di Cello, Angela Sacchinelli, Valentina Russo, Simona Trapasso, Fulvio Zullo & Michele Morelli

1.

Introduction

2.

Hyperandrogenism

3.

Menstrual disorders

4.

Infertility

5.

Long-term complications

6.

Conclusion

7.

Expert opinion

‘ Magna Graecia’ University, Cancer Center of Excellence “ Tommaso Campanella” of Germaneto, Department of Experimental and Clinical Medicine, Unit of Obstetrics and Gynaecology, Oncology Unit, Catanzaro, Italy

Introduction: Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disease among women of childbearing age. The clinical features are heterogeneous and vary in intensity. Hirsutism, menstrual disorders and infertility are the most frequent conditions observed; however, long-term complications (dyslipidemia, hypertension, cardiovascular disease, type 2 diabetes mellitus, endometrial cancer) are also often described. Each disorder may be managed by tailored strategies, employing sequential or combined pharmacological and/or non-pharmacological treatment. Areas covered: The authors review the drugs used for PCOS management and discuss new approaches. A systematic MEDLINE search regarding the randomized controlled trials, retrospective and observational studies about medical treatments of PCOS, the Cochrane library for reviews and also search for registered trials on ClinicalTrials.gov is performed. Expert opinion: A uniform treatment for PCOS patients does not exist. Clinicians should perform an accurate evaluation of patients’ characteristics, identifying the phenotypic target and, subsequently, the best-tailored treatment to manage one or more clinical issues. Lifestyle intervention should always be the first recommended approach unless other issues indicate that drug or hormonal interventions are superior. Keywords: cardiovascular risk, endometrial cancer, hyperandrogenism, infertility, menstrual disorder, oligoamenorrhea, polycystic ovary syndrome Expert Opin. Pharmacother. (2015) 16(9):1369-1393

1.

Introduction

Polycystic ovary syndrome (PCOS) is a hormonal condition characterized by reproductive, metabolic and psychological disorders, with a prevalence of 5 -- 15% in women of reproductive age, depending on the population and criteria applied in the analysis [1-6]. No universally accepted definition of PCOS is available, thus several diagnostic criteria have been consecutively proposed in order to obtain a standardized diagnosis (Table 1) [7-10]. During the Rotterdam Consensus Conference, the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) established that PCOS diagnosis might be performed after detection of two among the following criteria: i) oligo-anovulation; ii) clinical/biochemical signs of hyperandrogenism and iii) polycystic ovary (PCO) [9]. These diagnostic criteria have been widely accepted by scientific community for PCOS diagnosis in adult women [11]. Moreover, different criteria have been recently proposed to perform diagnosis in adolescent girl and perimenopausal/ menopausal women (Table 1) [11].

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In PCOS patients, weight loss and lifestyle modifications should be always be recommended since they improve metabolic status, ovulation regularity and prevent CV risks. Thus, every gynecologist should inform the woman that this approach is often more important than any drug. Each PCOS clinical manifestation (hyperandrogenism, irregular menses, infertility and long-term complications) can be managed by medical treatment, even if a combination of therapeutic options is often required. In absence of reproductive desire, COCs are the first-line approach in PCOS women presenting with moderate or severe hirsutism and/or menstrual abnormalities. Metformin is a first-line therapy in PCOS patients with oligomenorrhea desiring pregnancy or when COCs are contraindicated. It helps in restoring ovulation, in reducing body weight and in managing long-term metabolic complications. Conversely, it is not a first-line treatment for cutaneous manifestations (hirsutism, acne and androgenic alopecia). CC is the gold standard in mono-ovulation induction protocols. In this setting, metformin may be beneficial as adjuvant agent in obese infertile women, but cannot be considered as a first-line agent. The combination metformin plus CC represents the most effective strategy in CC-resistant women. Further trials are necessary to confirm the role of AIs. Low-dose gonadotropins represent an efficacious thirdline strategy for mono-ovulation induction. In IVF cycles, in order to eliminate OHSS risk, clinicians should choose GnRH antagonist protocols, trigger ovulation by GnRH agonist and choose if transfer fresh blastocysts or, in a safer view, freeze all blastocysts and transfer them in subsequent cycles. The induction of regular menstrual withdrawal bleeding with progestogens is a safe strategy for preventing EC; in particular, LNG-IUS is an efficacy device for hyperplasia treatment.

This box summarizes key points contained in the article.

PCOS clinical features are heterogeneous and vary in intensity; hirsutism, irregular menstrual cycle and infertility are the most frequent disorders observed in PCOS patients. Moreover, in PCOS women high risks of cardiovascular disease (CVD), type 2 diabetes mellitus (DM), metabolic syndrome and endometrial cancer (EC) have been reported. Given the heterogeneity of clinical manifestations, PCOS therapy is not uniform, but depends on phenotypic features and reproductive desire. First of all, weight loss and lifestyle modifications should be always recommended since they improve metabolic status, ovulation regularity and prevent cardiovascular (CV) risks [12], unless other issues indicate that drug or hormonal interventions are superior. Each disorder may be treated by tailored strategies, consisting in sequential or combined employment of pharmacological and/or not pharmacological treatment. Interestingly, each pharmacological treatment could be prescribed to manage one or more clinical symptoms. 1370

Notwithstanding the good scientific evidences and the well-recognized clinical efficacy, to our knowledge, there is no approved therapy for PCOS; accordingly, all drugs used in the management of PCOS are off-label. The aim of the current review was to analyze the pharmacological strategies, including off-label drugs, to manage the PCOS manifestations according to evidence-based data. 2.

Hyperandrogenism

Definition and diagnosis Hyperandrogenism is defined as a clinical and/or biochemical condition characterized by hirsutism, acne or alopecia, caused by hypersensitivity of peripheral androgen receptors [13] and/ or high concentration in circulating androgen (Figure 1) [9]. Hirsutism is the most common manifestation of hyperandrogenism, observed in about 70% of PCOS women [14,15]. On the other hand, acne and androgenic alopecia represent less clinical index of hyperandrogenism since they present with 20 -- 40% and 2%, respectively, of PCOS patients [16,17]. The treatment of hirsutism should improve not only the clinical manifestations, but also prevent and/or treat the possible associated metabolic derangements and, if possible, treat the underlying cause [18]. Non-pharmacological strategies (physical exercise and dietary advice) are usually adopted in order to avoid metabolic complications of the syndrome [11] but no convincing data support an improvement in hirsutism manifestations [12,18], thus a pharmacological approach is mandatory (Table 2). 2.1

Topic treatment Eflornithine is an irreversible inhibitor of L-ornithine decarboxylase, an enzyme that regulates cell growth and differentiation of the hair follicle. The common formulation has a concentration of 13.9% and it is effective in reducing reversibly and slowly the facial hair growth in up to 70% of patients [18,19]. Since the eflornithine reduces the hair growth, the laser treatment improves its efficacy by removing them, and that combination is effective in 8 weeks [19]. However, several side effects were described during this local treatment, such as skin irritation, stinging, burning, tingling and erythema [20]. 2.2

Systemic treatment A systemic pharmacological approach is required for mild or moderate/severe (Ferriman--Gallwey score > 15) and/or widespread hirsutism [21]. According to the severity of hyperandrogenism manifestations and clinical response to treatment, clinicians may choose among several protocols: single, sequential or combined therapy. 2.3

Hormonal therapy Combined oral contraceptives (COCs) are estro-progestin (EP) compounds widely employed as first-line treatment of hyperandrogenism in hirsute women who do not wish to become pregnant. 2.3.1

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Table 1. PCOS diagnostic criteria. Author

Year

Diagnostic criteria

Stein and Leventhal

1935

Simultaneous presence of: in vivo inspection of bilateral polycystic ovaries; oligoamenorrhea/infertility; hirsutism; obesity Presence of hyperandrogenism and/or hyperandrogenemia and chronic anovulation, after exclusion of hormonal disorders influencing androgen concentration and ovulatory function (thyroid dysfunction, hyperprolactinemia, androgen-secreting neoplasms or nonclassic adrenal hyperplasia) Almost two among oligo-anovulation; clinical/biochemical signs of hyperandrogenism; polycystic ovary (PCO)*; after exclusion of disorders with clinical characteristics same as PCOS Combination of hyperandrogenism with at least one of the following: ovarian dysfunction (including infrequent or irregular ovulation or anovulation) and PCO Adult: ESHRE/ASRM criteria Adolescent: presence of clinical and/or biochemical evidence of hyperandrogenism (after exclusion of other pathologies) in the presence of persistent oligomenorrhea Perimenopausal and menopausal women: well-documented long-term history of oligoamenorrhea and hyperandrogenism during the reproductive years

[7]

NIH

1990

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[8]

ESHRE/ASRM

2003

[9]

AEPCOS

2006

[10]

Endocrine Society [11]

2013

*At least one ovary with > 12 follicles measuring 2 -- 9 mm and/or an ovarian volume > 10 ml3. AEPCOS: Androgen Excess and PCOS Society; NIH: National Institute of Health; ESHRE/ASRM: European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine.

The efficacy is due to hormonal action at central and peripheral level: progestins and estrogens suppress the luteinizing hormone (LH) release and subsequently decrease ovarian androgen production; estrogens increase the liver production of sex hormone binding protein (SHBG), which decreases the plasmatic level of free androgens [22]. The reduced androgen synthesis from adrenal gland and the peripheral block of androgen receptors represent additional activities throughout COCs and act on hyperandrogenism [23]. Even if few randomized controlled trials (RCTs) have evaluated the efficacy of COCs in hyperandrogenism treatment [24], the available data show that both low- and highdose COCs containing ethinylestradiol (EE2) are effective in improving hirsutism in 60 -- 100% of patients [18,25-27]. Low-dose COCs, containing EE2 and antiandrogenic progestins, are the most employed drugs in clinical practice. The best EP compound to treat hyperandrogenism has not been

identified [11,28], but there is a wide consensus on avoiding progestin with high androgenic power [11,28]. Specifically, levonorgestrel (LNG) has been recently recommended as one of the progestagens with less thrombogenicity and devoid of androgenic effects [29]. Antiandrogenic progestins act by antagonizing androgen receptor (cyproterone acetate, drospirenone [DRSP], dienogest [DNG]) or inhibiting 5a-reductase activity (cyproterone acetate, chlormadinone acetate [CMA], ‘third-generation’ progestins [desogestrel, gestodene, norgestimate], DRSP and DNG) [22]. Even if EPs are effective in improving Ferriman--Gallwey score, as below detailed the outcome might change according to the progestin characteristics. DRSP is a progestogen derived from 17a-spirolactone. Unlike other progestins, it has anti-mineralocorticoid (aldosterone antagonistic) and antiandrogenic properties and is pharmacologically similar to endogenous progesterone (P). Antiandrogenic activity is due to the block of testosterone (T) binding to androgen receptors [30]. The androgen receptor antagonism may counteract androgen effects on facial hair, lipids and insulin [30]. DRSP 3 mg combined with 20 or 30 µg EE2 is effective in improving hirsutism score and T, dehydroepiandrosterone sulfate and SHBG hormonal levels in normal-weight PCOS women [31]. The comparison between DRSP 3 mg/EE2 30 µg and desogestrel 150 µg/EE2 30 µg has shown that DRSP is better than desogestrel in improving clinical outcomes, inducing a reduction of hirsutism score of 33.3% persistent at 6 months after treatment [32]. Similarly, DRSP/EE2 pills are more effective in improving hirsutism signs than EP containing 2 mg CMA [33]. Moreover, it seems more effective on acne and seborrhoea than other EPs [34]. CMA and cyproterone acetate are potent, orally active progestogens, which have antiandrogenic instead of partial androgenic activity. They act mainly by blocking androgen receptors in target organs, but also reduce the activity of skin 5a-reductase, the enzyme responsible for converting T to the more potent androgen, 5a-dihydrotestosterone, in sebaceous glands and hair follicles. CMA and cyproterone acetate also suppress gonadotropin secretion, thereby reducing ovarian and adrenal androgen production [35]. CMA in hirsute women is efficacious in reducing hyperandrogenism symptoms, fat mass and improving lipoprotein panel [36,37], also in young non-obese women with PCOS [38]. Cyproterone acetate is the oldest progestin used for its antiandrogenic properties [22,39], commonly associated with EE2. Compared with placebo, cyproterone acetate induces a significant improvement in hirsutism [39]; but compared with other COCs no significant differences were observed [39]. In particular, a study comparing cyproterone acetate 2 mg/EE2 35 µg versus desogestrel 0.15 mg/EE2 30 µg has shown similar efficacy in reducing hirsutism [40]. Similarly, no significant differences were observed between cyproterone acetate 2 mg/ EE2 35 µg and DRSP/EE2 [41,42], even if after 12 months of

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HYPOTHALAMUS -

-

GnRH

GnRH +

+ -

FSH

PITUITARY GLANDS

LH

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+

+

GRANULOSA CELLS + + +

OVARY

TECA CELLS + +

Circulating free androgens

Androgens Inhibin

-

Progestins +

Estradiol

SHBG

Figure 1. Hypothalamus--pituitary--ovary axis. FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; SHBG: Sex hormone binding protein.

Table 2. Pharmacotherapy for hyperandrogenism management in PCOS women. Drug

Administration

COCs DRSP CMA Cyproterone acetate

Low-dose COCs containing EE2/ antiandrogenic progestins are administered since the 1 day of menses for at least 6 months. DRSP 3 mg combined with EE2 20 or 30 µg CMA 2 mg plus EE 30 µg

Antiandrogens Spironolactone Finasteride Flutamide

Eflornithine ISDs Metformin Thiazolidinediones

Safety, limit and side effects

Avoid progestin with high androgenic power (i.e., LNG) COCs employment was not related to a significant impairment on glucose tolerance Products containing third-generation progestins, DRSP or cyproterone acetate represents a safe treatment in PCOS patients with regular CV risk. Clinician should pay attention to patient characteristics before starting any hormonal therapy, especially in adolescents, hypertensive women and smokers Spironolactone induces polyuria, nicturia, iperkaliemia, Daily dose of 200 mg hypotension Daily dose of 5 or 7.5 mg Flutamide induces gynecomastia, breast pain, dry skin, fatal liver Daily dose of 250 -- 500 mg toxicity All antiandrogens have a teratogenic effect on genital of fetus (feminization of male foetuses) Topic application at the formulation of 13.9% Efficacy disappears just after 8 weeks; skin irritation, stinging, burning, tingling and erythema Daily dose 1500 -- 2250 mg Metformin assumption induces gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominal bloating. Thiazolidinediones increase body weight

COCs: Combined oral contraceptives; CMA: Chlormadinone acetate; CV: Cardiovascular; DRSP: Drospirenone; EE2: Ethinylestradiol; ISDs: Insulin-sensitizing drugs; LNG: Levonorgestrel.

treatment EP-containing cyproterone acetate seems to be more effective to treat clinical hirsutism [42,43]. Estradiol valerate (E2V) is a novel estrogen similar to 17bestradiol (E2) and a shorter half-life than EE2, thus it might impact fewer lipid and glucose metabolism and a decreased risk for thromboembolic or CV complications [44]. A small preliminary observational study suggested that the E2V/ 1372

DNG exerts a positive influence on acne and hyperandrogenism in PCOS women with mild or moderate acne, after 1-year of treatment [45]. However, larger long-term RCTs are needed to confirm whether E2V/DNG offers any advantage over other COC formulations, for the treatment of acne [46]. PCOS women have per se an increased CV risk, thus clinician should evaluate patients’ characteristics (hypertension,

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PCOS: chemical pharmacotherapy

smoking, DM, obesity) before starting any hormonal therapy [47]. Preliminary data show that EPs containing thirdgeneration progestins, DRSP or cyproterone acetate, are safe for lean PCOS [48,49]. The addition of spironolactone to CMA/EE2 30 µg does not reduce CV risk in young PCOS women [50]; conversely, in lean PCOS women EE2/DRSP plus spironolactone therapy increases high-sensitivity C-reactive protein (CRP) and homocysteine levels after 6 months [51]. Some studies have shown that third-generation progestins induce mild increase in blood pressure [32]; and compared with second-generation COCs (such as LNG), these compounds increase the risk of non-fatal venous thromboembolism [52-54]. No data are available about the long-term action of COCs on glucose tolerance in both non-diabetic and diabetic women with PCOS. Interestingly, a meta-analysis performed by Lopez et al. [55] concluded that COCs do not impair significantly glucose tolerance. Given these results, the American Diabetes Association and the Centers for disease Control and Prevention declared that COCs are not contraindicated in women with DM without CV complications [56,57]. Concerning the efficacy of EP in obese and thin PCOS women, some authors did not detect any difference in terms of hirsutism improvement [58-60], even if Cibula et al. [61] showed that obese PCOS patients have less improvement in terms of hirsutism than thin women. Given the lack of conclusive data about efficacy of EPs in PCOS women with different body mass index (BMI), an in progress trial (NCT01360996) [62] is comparing the efficacy of 6 months of low-dose COC (DRSP 3 mg/EE2 20 µg) on androgen profiles and cardiometabolic measures. Antiandrogens Antiandrogens are the most effective drugs currently available for the hirsutism management; they should be applied for moderate/severe hirsutism; moreover, they could be administered after 6 months of COCs or after COCs failure [11,21,63]. The lowest effective dose should be recommended, particularly if a long-term treatment is planned; in many cases, the dose will be decreased after 3 -- 6 months of therapy at high doses [21]. Given the mechanism of action, antiandrogens are divided in two families: androgen receptor blockers (flutamide, spironolactone) and 5a-reductase inhibitors (finasteride). As already detailed, cyproterone acetate and DRSP are described among EP compounds (see above). Spironolactone mediates its antiandrogenic effects via multiple actions, including the following: i) direct blockade of androgens from interacting with the androgen receptor, representing a weak partial agonist with the capacity for both agonist and antagonist effects [64,65]; ii) inhibition of 17ahydroxylase and 17,20-desmolase enzymes in the androgen biosynthesis pathway, which in turn results in decreased T and dihydrotestosterone (DHT) levels [66,67]; iii) inhibition 2.3.2

of 5a-reductase, even if there are conflicting data on the ability of spironolactone to affect this enzyme [68-71]; iv) acceleration of the rate of metabolism/clearance of T by enhancing the rate of peripheral conversion of T to E2 [66]. Spironolactone has a dose-dependent efficacy, prescribed at a daily dose of 100 or 200 mg. Given its diuretic action, polyuria, nicturia, hyperkalaemia and hypotension are frequently described; thus it should be prescribed carefully in women with renal impairment [20]. Finasteride is a 5a-reductase inhibitor, which prevents the conversion of T to DHT [72]. Finasteride is usually prescribed at the dose of 5 mg, although the dose of 7.5 mg seems to be more effective compared with 5 mg, while no differences were detected between 2.5 and 5 mg [73]. Flutamide is a non-steroidal antiandrogens, or ‘pure’ antiandrogen, and has no steroidal effects. It acts by inhibiting in a dose-dependent manner the androgen receptor [74]. Flutamide is administered at the dose of 250 -- 500 mg/day. It provides dose-related adverse events such as breast pain and dry skin and, also fatal liver toxicity has been described [75]. In adolescents, side effects can be easily avoided if a dose < 125 mg/day is used [21]. Compared with placebo, flutamide 250 mg/day, finasteride 5 mg/day or spironolactone 100 mg/day induces a significant improvement in hirsutism outcomes [76]. Even if several authors have not observed any difference among antiandrogenic drugs in terms of clinical hyperandrogenism resolution [76-80], some data show that spironolactone 100 mg daily has higher efficacy in hirsutism treatment than finasteride 5 mg/day or cyproterone acetate 12.5 mg/day [81]. Controversial data have been published about flutamide efficacy. Several studies have shown that flutamide at 250 -- 750 mg/day has similar efficacy to spironolactone 100 mg/day and finasteride 5 mg/day [25,76,78,79,82,83]; while a limited number of studies observed a higher efficacy of flutamide than finasteride [84,85], cyproterone or gonadotropinreleasing hormone (GnRH) agonist [86]. Based on these considerations, it cannot be considered as a first-line drug. Interestingly, compared with spironolactone alone, the combination spironolactone plus finasteride seems more effective [87], but further studies should be performed. Lastly, in a recent RCT, the effectiveness of the administration of intermittent low-dose finasteride (2.5 mg every 3 days for 6 months) in young PCOS patients has been evaluated, showing that this regimen has similar efficacy of the continuous one but it is safer and less expensive [88]. All antiandrogens have a teratogenic effect, due to the block of androgen receptors that induces a feminization of male foetuses. Thus, during treatment period, patients should use adequate contraception method; the association with COCs is an option that might potentially offer synergistic effects. In case of contraindications of hormonal contraception (i.e., risk for thrombophilia, heavy smokers older than 35 years), contraception must be assured by using an intrauterine device or by surgical sterilization [18].

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2.3.3

Insulin-sensitizing drugs

Metformin and thiazolidinediones are insulin-sensitizing drugs (ISDs), which act by improving insulin sensitivity with following reduction in serum androgen concentration. All guidelines do not suggest insulin sensitizers to treat hirsutism [11,20], however, several studies evaluated their employment in hyperandrogenism reduction. Thiazolidinediones (pioglitazone and rosiglitazone) improve peripheral action of insulin. Available data [20,89-91] have shown a reduction in Ferriman--Gallwey score and androgen serum levels in adult and young PCOS women, without significant difference in terms of Ferriman--Gallwey scores compared with metformin [92]. However, glitazones do not have any role in PCOS treatment nowadays because of the serious side effects (such as CV and ischemic [93] and bladder cancer [94] risks). Metformin is a biguanide having pleiotropic insulinsensitizing actions not only at liver, skeletal muscles and adipose tissue, but also at ovarian site. It acts by 5a-AMPactivated protein kinase pathway, a kinase regulating energy metabolism [95], and facilitates the translocation of glucose transporters from intracellular sites to the plasma membrane [95], favoring the passage of glucose into the cell and so reducing glycemia levels. Metformin improves fasting and glucose-stimulated insulin, reduces ovarian androgen production, increases SHBG levels and subsequently reduces T and androstenedione (A) serum levels [95]. Several authors have evaluated metformin efficacy on hyperandrogenism [96-102]; these data showed a reduction of metformin at short-term (12 weeks of treatment) [103], but no long-term follow-up are available. In particular, metformin at the dose of 2250 mg/day reduces free T, A and LH, improving Ferriman--Gallwey score of 30% [103]. The ISDs are effective in obese PCOS women [104], however, controversial results have been published about metformin efficacy in non-obese non-insulin-resistant patients [105,106]. Moreover, compared with COCs and antiandrogens, a recent systematic review and meta-analysis of RCTs [107] showed that ISDs induce fewer effects on hirsutism. The most frequent adverse events due to metformin assumption are gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominal bloating), while a less risk of lactic acidosis has been described [20]. Among the ISDs used in the treatment of cutaneous disorders, there is myo-inosiol (MYO), an iso-form of inositol, belonging to the vitamin B complex. MYO is a simple and safe treatment that ameliorates the metabolic profile of PCOS patients improving ovarian function, metabolic and hormonal parameters [108]; its isoform, D-chiro-inositol (DCI), reduces hirsutism and acne after 6 months of therapy, but further data are needed in order to confirm these preliminary results. 1374

Currently, a RCT (NCT01791647) is recruiting obese PCOS patients in order to compare the efficacy of metformin 1500 mg/day versus MYO 1500 mg/day in terms of hirsutism score, menstrual pattern and metabolic evaluation [109]. Other drugs No studies have evaluated the long-term use of depot or intermittent oral medroxyprogesterone acetate in order to treat hirsutism [20]. GnRH agonists (leuproreline acetate, triptoreline) inhibit LH and follicle-stimulating hormone (FSH) release, which induce the suppression of ovarian androgen production and improve Ferriman--Gallwey score [28]. Compared with EP compounds [110,111] and antiandrogens [112], no significant improvement in hyperandrogenism resolution has been detected, but severe complications related to hypoestrogenism have been described, thus they cannot be used as first-line treatment. Concerning the use of glucocorticoids, inconsistent studies about safety and efficacy are available [113,114]; however, some data show that they are less effective than COCs or antiandrogens [18]. Ketoconazole, an adrenal enzyme inhibitor, ameliorates hirsutism but the frequent side effects limit its use [25]. Statins (atorvastatin, rosuvastatin, simvastatin) [115] and anti-obesity drugs (orlistat) [116] were found to reduce circulating androgen levels in patients with PCOS. In particular, there are no good evidences that statins improve menstrual regularity, spontaneous ovulation rate, hirsutism or acne, either alone or in combination with the COCs at short- and long-term [117]. 2.3.4

Combined therapy International guidelines [16] recommend that after 6 months of EP treatment without hirsutism improvement, a combined therapy of EP plus antiandrogens should be performed. Even if Kelekci et al. [118] did not show any effect, several RCTs [119-121] have shown that after 1 year of follow-up the combination of flutamide and EPs is more effective than EPs alone in improving hirsutism [18,122]. These data suggest that both finasteride and spironolactone added to COCs, containing small doses of cyproterone acetate, might provide additional significant clinical benefit in the treatment of hirsutism in PCOS women [21,123]. Concerning the combination metformin plus COCs or flutamide, controversial results are available. Fruzzetti et al. [124] have investigated the efficacy of EE2-DRSP plus cyproterone acetate (12.5 mg/day) or metformin (1500 mg/day) in normal weight women with PCOS, metformin provides significant benefit on selected CV risk factors, while cyproterone acetate abolishes this positive effect. The combined therapy metformin-COCs in PCOS non-obese women improves hyperandrogenism and insulin resistance state [51]. 2.3.5

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Table 3. Pharmacotherapy for menstrual disorders in PCOS women. Drug

Administration

Safety, limit and side effects

Progestins

5 -- 10 mg daily for 10 -- 12 days starting from 14 -- 16 day of cycle

Protective action on endometrial cancer. Abnormal bleeding in 50 -- 89% of women; coagulopathy, depression, hydric retention have been described

COCs

Low-dose COCs containing EE2/ antiandrogenic progestins since the 1 day of menses for at least 6 months

COCs may increase triglyceride levels

ISDs Metformin Thiazolidinediones MYO

Low starting dose, a subsequent increment until 1500 -- 2500 mg 1500 mg/day

Metformin assumption induces gastrointestinal symptoms (diarrhea, nausea, vomiting, abdominal bloating. Thiazolidinediones increase body weight

COCs: Combined oral contraceptives; EE2: Ethinylestradiol; ISDs: Insulinsensitizing drugs; MYO: Myo-inositol.

The combination metformin plus flutamide provides beneficial effect [98,107,125-127], however, the embryotoxicity limits their use. The addition of low-dose spironolactone to metformin induces a higher reduction of clinical and biochemical hyperandrogenism than metformin alone [128,129]. Compared with metformin alone, the combination of metformin/statin after 12 weeks of treatment might lead to an improvement of hyperandrogenism and lipid profile in patients with PCOS [130]. Thus, the combination of antiandrogens with COCs or metformin is effective in improving androgenic parameters, but no long-term follow-up data are available.

3.

Menstrual disorders

Definition and diagnosis Menstrual disorders (oligo-amenorrhea, abnormal uterine bleeding) affect about 75 -- 85% of PCOS population. The main mechanism related to menses disorders is the chronic anovulation, which induces a prolonged estrogens stimulation of endometrium without P withdrawal (Figure 1) [131]. 3.1

Since in PCOS women diet and physical exercise are effective in improving ovulation and menstrual regularity [11], they should be always recommended [11]; however, the pharmacological approach is mandatory (Table 3). Hormonal therapy Progestins are administered to treat menstrual disorders in oligomenorrhoic PCOS women. Cyclical progestogens are used during the second half of the menstrual cycle, in order to induce a regular withdrawal bleed [131], while continuous progestogens is used to induce endometrial atrophy and hence to prevent estrogen-stimulated endometrial proliferation [131]. Notwithstanding a protective endometrial action from cancer, some adverse events, such as CV complications, depression, hydric retention, have been described; moreover, they do not affect coagulation and are useful especially in women with thrombophilia. COCs are the first-line pharmacological strategy for menstrual disorders in PCOS women without reproductive desire [11,20]. According to available evidences, all commercially available EPs are safe and effective to induce regular bleeding and decrease intra-cyclic spotting rate. Since hormonal treatment is tailored to patients’ phenotypic characteristic, usually clinicians prescribe low-dose EP with antiandrogenic progestins [132]. Progestogens and estrogens and progestogens in combination are widely used in the management of irregular menstrual bleeding, but the regime, dose and type of P used vary widely, with little consensus about the optimum treatment approach [131]. 3.2

Insulin-sensitizing drugs Thiazolidinediones (pioglitazone and rosiglitazone) improve menstrual disorders [133]; however, their employment is widely limited in the clinical practice since they increase body weight in obese PCOS [133,134]. Metformin represents the most important and effective ISDs used to treat oligo-amenorrhea not only in obese and insulin-resistant PCOS subjects [97,135,136], but also in PCOS women with normal glucose tolerance [96]. Even if there is no consensus about the most effective dose, several metaanalysis concluded that the therapy should be performed according to an incremental dose protocol (low starting dose, and subsequent increment until 1500 -- 2500 mg) [133,137-139]. Trials directly comparing metformin with COCs have shown that the biguanide is not effective as hormonal compound for menstrual cycle regulation both in obese [58] and non-obese [59]. Among ISDs, several papers evaluate MYO effects on oligo-amenorrhea in PCOS patients [108,133,140-143], suggesting that MYO and its isoform DCI might restore spontaneous ovarian activity, hence menses regularity and fertility. The comparison between metformin and MYO has not shown any differences in terms of menstrual regularity [142]. 3.3

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Figure 2. Macroscopic image of a polycystic ovary.

Other drugs N-Acetyl-cysteine (NAC) inhibits oxidative stress involved in PCOS pathogenesis, thus is employed in the treatment of menstrual irregularity. Moreover, compared with metformin, the NAC for 24 weeks induce comparable effects on menstrual irregularity [144]. Similarly, the association of NAC plus inositol plus folic, regardless of insulin-resistance state, seems to improve ovarian function [145]. 3.4

feedback of estrogens and increasing endogenous FSH-LH secretion [150]. CC is a low-cost drug at low risk of multiple pregnancies and ovarian hyperstimulation syndrome (OHSS); the starting dose is 50 mg daily for 5 days during the precocious follicular phase. The dose is eventually increased by 50 mg per cycle up to 150 mg/day [63] but CC should be continued for no longer than 6 months [149]. The dose of 150 mg is considered the best one, since it is associated with 75% of ovulation rate. At these regimens, ovulation occurs in 60 -- 85% of patients, with a pregnancy rate of 30 -- 50% after six ovulatory cycles [150]. During CC treatment, follicle development is evaluated by serial ultrasonography scans. When the follicle reached > 18 mm in diameter, the trigger of ovulation is performed by administration if 10,000 international unit (IU) human chorionic gonadotropin (hCG), and time intercourse are scheduled. Cycle cancellation is advised if more than two follicles are > 16 mm or one follicle is > 16 mm and two other follicles are > 14 mm [136]. The addition of intrauterine insemination (IUI) to the first three cycles of CC ovulation induction does not improve reproductive outcomes for PCOS woman where anovulation is the only cause of infertility. A RCT comparing three consecutive cycles of CC ovulation induction with either IUI or timed intercourse as first-line treatment for anovulatory infertility in therapy-naive women non-obese PCOS, indeed, showed comparable results in clinical pregnancy rate per cycle (8.5 vs 7.9%; p = 0.26) or per woman (23.6 vs 22.1%; p = 0.33), miscarriage rate per pregnancy (18.1 vs 19.0%; p = 0.31) and live-birth rate per woman (19.3 vs 17.9%; p = 0.33) [151]. If ovulation cannot be induced at doses of 150 mg/day, the patient is considered to be clomiphene resistant and alternative treatment has to be scheduled (see below). Insulin-sensitizing drugs Few studies evaluated the efficacy of thiazolidinediones in ovulation induction protocols. Compared with placebo, rosiglitazone improves ovulation rate (odd ratio [OR] 31; 95% CI: 3.76 -- 255.3) [105,133], even if an increased BMI is observed [105,133]. Metformin is an effective treatment for anovulatory infertility in women with PCOS and is associated with restored monofollicular ovulation and low multiple pregnancy rates [11]. Even if some preliminary data had not demonstrated any efficacy [138,139], a recent Cochrane showed that metformin significantly increases ovulation rate (OR: 2.31; 95% CI: 1.52 -- 3.51) and clinical pregnancy rate (OR: 2.31; 95% CI: 1.52 -- 3.51) compared with placebo, even without difference in terms of live-birth (OR: 1.80; 95% CI: 0.52 -- 6.16) [133]. Moreover, Morin-Papunen et al. have published a multicenter, double-blind, RCT [152], which compared 3 months pre-treatment with metformin and placebo, and showed that 4.3

4.

Infertility

Definition and diagnosis Anovulatory infertility is a condition due to absence or anomalies in ovulatory cycles [146], accounting for 25 -- 40% of all infertile conditions [147,148] and for 70 -- 90% of all ovulatory disorders (Figure 2) [11]. In anovulatory overweight/obese PCOS patients, lifestyle interventions (diet, exercise and weight loss) are short-term approaches that may restore ovulation, improve response to ovulation induction agents and have a positive impact on pregnancy outcomes [9,149]. However, in women with PCOS pharmacological strategies represent the best approach in order to obtain simple or multiple ovulations (Table 4). 4.1

Clomiphene citrate Clomiphene citrate (CC) restores ovulation by blocking estrogen receptor at hypothalamic level, reducing the negative 4.2

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Table 4. Pharmacotherapy for infertile PCOS women. Drug

Administration

Safety, limit and side effects

CC

Starting dose is 50 mg daily for 5 days during the precocious follicular phase. The dose is eventually increased by 50 mg per cycle up to 150 mg/day Low starting dose, a subsequent increment until 1500 -- 2500 mg

Low-cost drug at low risk of multiple pregnancies and OHSS

Metformin

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AIs Letrozole Anastrozole Gonadotropins

Gonadotropin in IVF/ICSI cycle Long protocol GnRH agonist

GnRH antagonist protocols

No major adverse effects (miscarriage and multiple pregnancies); gastrointestinal disturbances in about 30% of patients, limiting the compliance to treatment Higher incidences of fatigue and dizziness

Doses between 2.5 and 5 mg/day for 5 days starting on day 3 of the menstrual cycle Daily dose of 1 mg for 5 days ‘Conventional step-up’ protocol: daily stimulation with a gonadotropin starting from a dose of 75 IU ‘Low-dose step-up’ protocol: daily administration of 37.5 -- 50 IU FSH, afterwards increase of 25 -- 37.5 IU at 7 -- 14 day intervals until follicular development is observed ‘Very low dose’ and ‘ultra-low dose’ protocols: daily starting dose 37.5 IU or less, with secondary increase according to follicle response until a maximum of 225 IU/day.

Cycle cancellation is advised if more than two follicles are > 16 mm or one follicle is > 16 mm and two other follicles are > 14 mm

Depot or daily formulation since mid-luteal phase or the GnRH antagonist significantly reduces the risk of OHSS early follicular phase. 10 -- 14 days later, after detection of E2 concentration < 20 -- 30 pg/ml, no recruited follicles and endometrial thickness < 6 mm, gonadotropin injection can be administered FSH treatment is started on day 2 -- 3 of cycle; daily s.c. administration of 0.25 mg antagonist is initiated when at least one of the following criteria are fulfilled: at least one follicle measuring > 13 mm; serum E2 levels > 600 pg/ml; serum LH levels > 10 IU/l. Ovulation can be triggered by hCG (standard) or by GnRH agonist (in presence of signs of hyper-response), in order to eliminate the risk oh OHSS

AIs: Aromatase inhibitors; CC: Clomiphene citrate; E2: Estradiol; GnRH: Gonadotropin-releasing hormone; OHSS: Ovarian hyperstimulation syndrome; s.c.: Subcutaneous.

metformin increased not only ovulation, but also live-birth rates (41.9 vs 28.8%; p = 0.014, for metformin and placebo, respectively) and pregnancy rates (53.6 vs 40.4%; p = 0.006, for metformin and placebo, respectively). Similar results were obtained also before in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles, in which metformin treatment for 12 weeks in non-obese PCOS women significantly increases pregnancy (50.0 vs 33.3%; p = 0.0391) and live-birth rates (48.6 vs 32.0; p = 0.0383) compared with placebo [153]. To date, no consensus is available about dose and duration of metformin administration; as far as this is concerned, a trial (NCT00501904) [154] is currently recruiting participants in order to evaluate its clinical efficacy according to duration of administration in infertile PCOS ovulating under treatment. Even if no major adverse effects such as miscarriage and multiple pregnancies have been demonstrated, metformin

induces gastrointestinal disturbances in about 30% of patients, limiting the compliance to treatment [133]. In the comparison of CC and metformin as first-line agent for ovulation induction in PCOS patients, a RCT, enrolled 626 infertile PCOS women, demonstrated the superiority of CC in achieving live-birth compared with metformin (22.5 vs 7.2%, for CC and metformin, respectively), without significant (p = 0.31) benefit of combined therapy compared with CC alone [155]. In addition, the rates of first-trimester pregnancy loss did not differ significantly among the groups, while the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the CC group (39.5%; p = 0.002) or the combination-therapy group (46.0%; p < 0.001) [155]. These data have been thereafter confirmed by several studies. In a systematic review and meta-analysis, Siebert et al. [156]. demonstrated a reduction in the live-birth rate in the

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group of patients treated only with metformin (OR: 0.48; 95% CI: 0.31 -- 0.73; p = 0.0006) compared with CC [156]. In the same year, Tang et al. [133] showed that pregnancy (OR: 0.34; 95% CI: 0.21 -- 0.55) and live-birth rates (OR: 0.3; 95% CI: 0.17 -- 0.52) are higher for CC versus metformin in obese women, without differences in multiple pregnancy rates between treatments. In non-obese anovulatory PCOS women, meta-analytic results [133,157] showed no significant difference in pregnancy and live-birth rates for metformin versus CC and a recent paper concluded that there is no evidence to establish a difference between metformin and CC in terms of ovulation, pregnancy, live-birth, miscarriage and multiple pregnancy rates in non-obese PCOS women [158]. Contrary to previous paper [155], more recent systematic review and meta-analysis [133,156,159] demonstrated that the co-administration of metformin plus CC is superior to CC alone as primary method to induce ovulation and to achieve pregnancy in PCOS, especially in older and viscerally obese patients [133,156,159]. Creanga et al. [160] first showed an increase in ovulation (OR: 4.39; 95% CI: 1.94 -- 9.96) and pregnancy (OR: 2.67; 95% CI: 1.45 -- 4.94) rates by adding CC to metformin. Tang et al. [133] confirmed that clinical pregnancy rates improved in patients treated with metformin and clomiphene versus CC alone (OR: 1.51; 95% CI: 1.17 -- 1.96), although the combined strategy does not improve live-birth rates (OR: 1.16; 95% CI: 0.85 -- 1.56) [133]. According to available evidences, DCI does not improve ovulation rate [133,141] compared with placebo; no data are available about live-birth and clinical pregnancy rates. The NAC is a mucolytic drug acting as ISD, increases the insulin secretion by the b-cells of the pancreas and induces an increased sensitivity to the organism itself [145]. Preliminary data showed that the addition of NAC to CC is effective in inducing ovulation in PCOS compared with anti-estrogen alone [161], but further studies are needed to confirm these observations. Aromatase inhibitors Aromatase inhibitors (AIs) (letrozole, anastrozole) are a new class of drugs, introduced for ovulation induction in 2001. Over the last 10 years, clinical trials have reached different conclusions on the efficacy of letrozole when compared with CC. AIs block the conversion of T and A to E2 and estrone, respectively. The decrease in estrogenic activity releases the hypothalamus from negative feedback, allowing for the release of FSH and LH [63]. Letrozole is administered in doses between 2.5 and 5 mg/day for 5 days starting on day 3 of the menstrual cycle [63], while anastrozole is administered at the daily dose of 1 mg for 5 days. No RCTs compared AIs versus placebo or no treatment in women with PCOS [162]. Meta-analyses of six RCTs comparing letrozole and CC demonstrated that AIs improves the ovulation rate per patient (OR: 2.90; 95% CI: 1.72 -- 4.88; 4.4

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p < 0.0001), but no statistical difference for the ovulation rate per cycle, pregnancy, live-birth, multiple pregnancy or miscarriage rates were found [162]. These results have been confirmed in a recent Cochrane Review evaluating the effectiveness and safety of AI used alone or with other medical therapies for ovulation induction in PCOS patients [163]. When live-birth was considered, the comparison ‘letrozole vs placebo’ resulted inconclusive. In the comparison ‘letrozole vs CC’, the birth rate was higher in the letrozole group than CC one (OR: 1.63; 95% CI: 1.31 -- 2.03), while no difference was observed between letrozole and laparoscopic ovarian drilling (LOD) [163]. Letrozole was also related to higher pregnancy rate compared with CC after both time intercourse and IUI [163]. Similarly, a recent large National Institute of Health-sponsored, multicenter, double-blind, RCT showed a superiority of letrozole over CC in live-birth rate in women with PCOS, with a comparable safety and tolerance profile between drugs [164]. Legro et al. [165] recently showed in a double-blind, multicenter trial that women who received letrozole for up to five treatment cycles had more cumulative live-births than those who received CC (27.5 vs 19.1%; p = 0.007), without significant differences in overall congenital anomalies. The cumulative ovulation rate was higher with letrozole than CC (61.7 vs 48.3%; p < 0.001) without significant differences between groups in pregnancy loss or twin pregnancy [165]. Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness [165]. Other drugs There are insufficient data to determine the role of ketoconazole, bromocriptine, hCG or hormone supplementation in association with CC versus clomiphene alone in anovulatory normoprolactinemic women [166]. In the comparison CC versus tamoxifen, only one RCT concluded that CC is more successful than tamoxifen as a first-line therapy for ovulation induction in women with PCOS [167], but data are insufficient for allowing conclusions. 4.5

Clomiphene resistance In CC-resistant PCOS women, alternative clomiphene regimens and drug combinations have been developed. The extending CC treatment (100 mg daily starting on day 2 of menses for 9 days) [168] and the luteal phase administration of CC (100 mg of CC daily starting the next day after finishing MPA) [169,170] represent two efficacious strategy of clomiphene administration employed for enhancing ovarian sensibility to the anti-estrogen. Considering these evidences, a RCT (NCT02024984) [171] is recruiting patients in order to compare luteal phase (early) versus the conventional follicular phase (late) administration of CC with regard to ovarian response. A new modality of administration, defined stair-step protocol, has been also proposed [172,173]. In the stair-step protocol, 4.6

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patients were treated with CC 50 mg/day for 5 days and in non-responsive patients the dosage was increased to 100 mg/day for 5 days in the same cycle [173]. Both retrospective [172] and a more recent RCT report that even if no advantages in terms of ovulation and pregnancy rates were observed over the traditional protocol, the duration of treatment was significantly shorter in stair-step protocol, without any differences in the systemic side effects between the groups [173]. In order to improve ovarian sensibility to CC, several pretreatment approaches were also evaluated. Among nonpharmacological strategy in overweight/obese PCOS women, lifestyle modifications [174] and LOD [175] improved ovarian response to CC. Dexamethasone pre-treatment has shown that it increases ovulation and pregnancy rates in CC-resistant women with PCOS, without any difference in multiple pregnancy and side effects [166]. Similarly, a benefit of CC plus EPs in pregnancy and ovulation rates was observed, without evidence of miscarriage and multiple pregnancy rates [166]. Compared with CC alone, combination of coenzyme Q10 (CoQ10) [176] or L-carnitine [177] plus CC improves ovulation and clinical pregnancy rates, with an acceptable patient tolerability. Simvastatin pre-treatment in CC-resistant PCOS women has no favorable effect on ovulation and pregnancy rates [178] As far as metformin pre-treatment in CC-resistant PCOS women is concerned, there are insufficient data to determine whether short-course (< 4 weeks) is as effective as the conventional long course (4 weeks or more) before initiation of CC [179]. Compared with CC alone, the combination of CC and metformin induces higher ovulation and pregnancy rates [138,139,160,180]. This regimen is also more effective than LOD [181] and letrozole [182] for inducing ovulation and obtaining pregnancy. Metformin alone to induce ovulation in CC-resistant PCOS women did not demonstrate any significant effect compared with placebo in terms of ovulation and pregnancy rates [183]. On the contrary, metformin led to higher live-birth rates than LOD [184]. The co-administration metformin plus NAC did not show any beneficial effects in ovulation induction [185], but further data are necessary. AIs employment in the ovulation induction in CC-resistant PCOS women was widely evaluated. Even if no significant differences were detected in terms of ovulation (62 vs 63.4%), pregnancy (12.2 vs 15.1%) and miscarriage rate for letrozole and anastrozole, respectively [186], letrozole at the dose of 2.5 mg/day for 10 days was the AI most employed in the clinical practice [162]. Results obtained from the comparisons between letrozole and placebo in CC-resistant PCOS women are debatable [162,186-190]. Some authors [186-190] have confirmed the positive action of letrozole in terms of ovulation, endometrial action and pregnancy rate, whereas a single high-quality RCT [191], powered for detecting difference in ovulation

rate, has shown that letrozole is superior to placebo in second-line therapy in terms of ovulation rate, but does not improve pregnancy or live-birth rate. A systematic review and meta-analysis [162] concluded that letrozole does not improve pregnancy or live-birth rates compared with placebo or with CC plus metformin in women with CC-resistant PCOS [162] and there is insufficient evidence to recommend letrozole in CC-resistant women. The evidence about the risk of congenital abnormalities by using AIs is unclear and these complications cannot be ruled out [162]. In the comparison letrozole versus LOD, Abu Hashim et al. [192] showed that letrozole 2.5 mg daily for up to six cycles in anovulatory CC-resistant PCOS patients were equally effective as LOD for inducing ovulation and achieving pregnancy. Recently, a RCT [193] comparing metformin plus letrozole and LOD in CC-resistant women demonstrated no difference in cycle regularity (p = 0.82), ovulation (p = 0.24), pregnancy rate (p = 0.32) and abortion rate (p = 0.51); however, a significant reduction in metabolic hormone and parameters was observed in metformin plus letrozole group [193]. 4.7

Gonadotropins Mono-ovulation protocols

4.7.1

Gonadotropins are second-line pharmacological strategy employed in mono-ovulation protocols in CC-resistant PCOS women or when alternative approaches (such as combination of metformin plus CC) are not efficacious [194]. Although the goal of FSH administration is recruiting a single follicle resulting in a singleton live-birth [136], the insulin-resistant state makes PCOS women susceptible to an excessive gonadotropin response, multiple pregnancies, cancelled cycle and OHSS [136]. In PCOS subjects, ovulation induction using gonadotropins is based on the physiological concept that initiation and maintenance of follicle growth may be achieved by a transient increase in FSH above a threshold dose for sufficient duration to generate a limited number of developing follicles [63]. Clinicians could prescribe human-derived (urinary [u], human menopausal gonadotropin [hMG], highly purified [hp] FSH) or recombinant (r) FSH. In mono-ovulation protocols, no significant differences in pregnancy rate between uFSH and hMG were detected, even if the urinary gonadotropin reduced OHSS development (OR: 0.20; 95% CI: 0.08 -- 0.46) [195]. The employment of urinary and recombinant drugs has comparable safety and reproductive outcomes (ovulation rate, singleton live-birth, pregnancy, miscarriage, multiple pregnancy, OHSS) [196]. Similarly, hpFSH is as efficacious as rFSH in obtaining ovulation (85.2 vs 90.9%, for hpFSH and rFSH, respectively) and pregnancy [197]. In PCOS women, gonadotropins can be administered according to the ‘conventional step-up’ protocol, consisting in a daily stimulation with a gonadotropin at the dose of 75 IU but considering the risk of excessive response to

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gonadotropins, the so-called ‘low-dose step-up protocol’ is recommended [136], since it gives more pregnancy rate and less OHSS/multiple pregnancy rates than conventional stepup, providing mono-follicular development in more than half of the women undergoing therapy [197]. The low-dose step-up protocol consists in a daily administration of 37.5 -- 50 IU FSH, afterwards increased of 25 -- 37.5 IU at 7 -- 14 days interval until follicular development is observed [63]. Very low-dose and ultra-low-dose protocols consist in a daily starting dose 37.5 IU or less, with secondary increase according to follicle response until a maximum of 225 IU/day. They induce uniovulation in 70% of cycles with a good conception rate [198]. Compared with classic step-down (starting dose 150 IU/day and subsequent reduction of daily units), sequential low-dose step-up (37.5 IU/day) and low-dose step-down protocols (75 IU/ day) using rFSH seem to be more effective in terms of pregnancy rate, without difference in rate of monofollicular development and OHSS [199]. During gonadotropin administration serial ultrasonographic evaluations of follicular growth is performed. When follicle has a diameter of 18 mm, 24 h after the last gonadotropin injection hCG is administered and time intercourse is scheduled. Cycle cancellation is advised if more than two follicles are > 16 mm or one follicle is > 16 mm and two other follicles are > 14 mm [136]. In the comparison CC versus low-dose step-up FSH, as first-line therapy in anovulatory women with PCOS, reproductive outcomes were higher in FSH treatment than CC in terms of pregnancy rate (30 vs 14.6%, respectively, p = 0.003), live-birth rate (52 vs 39%; p = 0.04), cumulative pregnancy rate (52.1 vs 41.2%; p = 0.021) and cumulative live-birth rate (47.4 vs 36.9%; p = 0.031) [200], although CC is more convenient and less costly than gonadotropins. Controlled ovarian hyperstimulation and IVF cycle

4.7.2

IVF cycles are recommended as third-line therapy for the management of infertility in PCOS patients, after failure of first- and second-line strategies [136] or in presence of male indications. The aim of the controlled ovarian hyperstimulation (COH) is to achieve a multifollicular ovarian development for subsequent egg retrieval, fertilization and production of embryos for transfer. The success rate of IVF is improved over time and, in 2005, 34% of cycles resulted in a clinical pregnancy while 28% of cycles in a live-birth [194]. After gonadotropin administration, the risk of OHSS in PCOS women is at least 10%, significantly higher if compared with a risk of 0.5 -- 4.0% observed in the general IVF population [201], but new strategies are now available to prevent this complication (see above). According to literature, no significant difference among gonadotropins (hMG, rFSH, hp-hMG) in terms of ongoing pregnancy or live-birth rates was demonstrated [202]. 1380

The standard protocol consists in a long protocol GnRH agonist in depot or daily formulation since mid-luteal phase (21 day of cycle) or the early follicular phase (2nd -- 3rd day of cycle). Ten to 14 days later, after detection of E2 concentration inferior to 20 -- 30 pg/ml, no recruited follicles and endometrial thickness < 6 mm, gonadotropin injection according to a step-down regimen can be administered. Serial ultrasonographic evaluation of follicles stimulation is performed. When follicles reached a diameter of 17 mm, 24 h after the last gonadotropin injection ovulation, triggering with 10,000 IU hCG is administered and pick-up is scheduled. A recent Cochrane review, comparing the GnRH antagonist with the long GnRH agonist protocol in women with PCOS undergoing IVF/ICSI treatment, did not show significant difference in live-birth (OR: 0.86; 95% CI: 0.69 -- 1.08) and ongoing pregnancy rates (OR: 0.87; 95% CI: 0.77 -- 1.00) [203]. Interestingly, compared with the GnRH agonist long protocol, all meta-analytic results demonstrated that GnRH antagonist significantly reduced the risk of OHSS [201,203,204]. In GnRH antagonist protocols, FSH treatment is started on day 2 -- 3 of cycle and daily subcutaneous administration of 0.25 mg antagonist is initiated when at least one of the following criteria are fulfilled: at least one follicle measuring > 13 mm; serum E2 levels > 600 pg/ml; serum LH levels > 10 IU/l. As soon as three follicles reaches a mean diameter of > 17 mm, 10,000 IU of hCG are administered. GnRH agonist may be used as a safer alternative to hCG for the ovulation trigger, especially if the freeze of all obtained embryos with transfer in a subsequent spontaneous cycle is planned [201]. Final oocyte triggering with GnRH agonist instead of hCG in fresh autologous GnRH antagonist IVF/ICSI treatment cycles prevents OHSS (OR: 0.15; 95% CI: 0.05 -- 0.47) but also reduces the live-birth rate (OR: 0.47; 95% CI: 0.31 -- 0.70) [205]. In women with donor-recipient cycles, on the contrary, the lower incidence of OHSS in the GnRH agonist group than in hCG group (OR: 0.05; 95% CI: 0.01 -- 0.28) is maintained, whereas no differences between groups in live-birth rate (OR: 0.92; 95% CI: 0.53 -- 1.61) or ongoing pregnancy rate (OR: 0.88; 95% CI: 0.58 -- 1.32) were found [205]. This allows the authors to conclude that GnRH agonist for the oocyte maturation trigger might be useful for those women who choose to avoid fresh transfers or who wish to freeze their eggs for fertility preservation. A recent retrospective study [206] concluded that serum E2, LH and P levels on the day after trigger, total number of mature oocytes or percent mature oocytes, fertilization, implantation, clinical pregnancy and live-birth rates were similar in PCOS women and other hyper-responders when final trigger was achieved by administering GnRH agonist in antagonist cycles. Currently, when an excessive ovarian response is encountered in PCOS stimulated women undergoing IVF in an

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antagonist regimen, the clinicians have two alternatives: the first one is to trigger oocyte maturation with a bolus of GnRH agonist and supplement the luteal phase with a small bolus of hCG and more intensive E2 and P supplementation than those used in the standard luteal phase support and transfer in the fresh cycle. The second option is to trigger with GnRH agonist and perform a total blastocysts freeze, again resulting in a complete elimination of OHSS and high ongoing pregnancy rates in the subsequent frozen-thawed transfer cycles [207]. Combined therapy Several combined strategies were evaluated in order to improve gonadotropin response in mono-ovulation protocol and COH. Ghanem et al. [208] demonstrated that, compared with uFSH alone, the combined approach (CC 100 mg/day for 5 days plus uFSH 37.5 IU/day) allowed higher ovulation rate (72.4 vs 34.2%; p < 0.001), lower total FSH dose and shorter stimulation duration. Similarly, in COH using CC associated with gonadotropin and GnRH antagonist versus conventional COH (without CC), no significant difference in live-birth, clinical pregnancy, miscarriage, endometrial thickness and number of oocytes retrieved was observed but significant reduction in OHSS (0.5 vs 4.1%; p = 0.01), consumption of gonadotropins and duration of COH is achieved [209]. The combined treatment metformin plus gonadotropins both in mono- and multiple ovulation induction in PCOS women was also studied. In a preliminary systematic review, Moll et al. [184] showed no evidence for a positive effect on live-birth of metformin when co-administered with FSH in IVF cycle (relative risk [RR]: 1.5; 95% CI: 0.92 -- 2.5) but fewer cases of OHSS (RR: 0.33; 95% CI: 0.13 -- 0.80) were registered under metformin [184]. In a systematic review and meta-analysis, Costello et al. [210] confirmed that the co-administration metformin-gonadotropin did not improve ovulation (OR: 3.27; 95% CI: 0.31 -- 34.72) or pregnancy (OR: 3.46; 95% CI: 0.98 -- 12.2) rates. More recently, a meta-analysis of seven RCTs [211] concluded that metformin improves live-birth (OR: 1.94; 95% CI: 1.10 -- 3.44; p = 0.020) and pregnancy (OR: 2.25; 95% CI: 1.50 -- 3.38; p < 0.0001) rates, and decreased cancellation rate (OR: 0.41; 95% CI: 0.24 -- 0.72; p = 0.002). Notwithstanding these encouraging results, further adequately powered RCTs are needed to confirm data. About ISD co-administration in COH protocol for IVF, Costello et al. [210] first concluded that metformin does not improve pregnancy (OR: 1.29; 95% CI: 0.84 -- 1.98) or live-birth (OR: 2.02; 95% CI: 0.98 -- 4.14) rates but reduces OHSS risk (OR: 0.21; 95% CI: 0.11 -- 0.41, p < 0.00001) [210]. These data were successively confirmed by a Cochrane Review of five RCTs, concluding that metformin treatment before or during IVF/ICSI cycles does not improve live-birth (95% CI: 0.27 -- 2.18) and clinical pregnancy rates (95% CI:

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4.7.3

0.39 -- 1.28), but decrease OHSS development (OR: 0.27; 95% CI: 0.16 -- 0.47) [212]. Contrary to previous conclusions [210,212], in a systematic review and meta-analysis of 10 RCTs, Palomba et al. [213] demonstrated that metformin administration in IVF/ICSI cycles increased implantation rate (OR: 1.42; 95% CI: 1.24 -- 2.75). In COH protocols, the response to metformin is widely conditioned by patients’ characteristics. Specifically, in PCOS patients at high-risk for OHSS, metformin significantly reduces not only the total OHSS (RR: 0.28; 95% CI: 0.11 -- 0.67), but also cancellation rates, even if the stimulation length and amount of gonadotropins are increased [214]. On the contrary, in PCOS women with reduced ovarian reserve (older than 35 years and/or with a basal FSH level > 10 IU/l), the co-treatment worsened the response to gonadotropin and its administration should be stopped before starting a COH [215]. Lastly, also in non-obese women with PCOS patients, metformin treatment for 12 weeks before and during IVF or ICSI provided beneficial effects in reproductive outcomes [153,216]. Considering the administration of COCs before gonadotropins, the extended hormonal pre-treatment does not improve the pattern of follicular growth nor the oocyte and embryo quality [217]. In IVF cycle, a preliminary RCT demonstrated that COCs plus long GnRH agonist and COC plus fixed GnRH antagonist protocols yield similar ongoing pregnancy rates (36.4 vs 35.9%; p > 0.05) [218]. The combination letrozole plus gonadotropin is a good alternative to CC in patients undergoing COH with GnRH antagonist. The administration of letrozole during the follicular phase increases clinical pregnancy rate and reduces the total gonadotropin dose required for ovarian stimulation [219]. Similarly, employed in high-risk patients during luteal phase, AIs drastically reduce estradiol levels with following reduction in OHSS development [219].

5.

Long-term complications

CV complications and diabetes 5.1.1 Definition and diagnosis 5.1

PCOS women are exposed to type 2 DM risk and long-term CV complications (increased blood pressure, endothelial dysfunction, reduced arterial compliance, central obesity, dyslipidemia, low-grade chronic inflammation, increased endothelin-1 and homocysteine) [220]. The high blood pressure and atherogenic lipid profile in women with PCOS may contribute to develop a non-fatal stroke and possibly coronary heart disease [221]. Clinicians should recommend lifestyle modifications (exercise combined with dietary change) as first-line approach to modify risk factor for CVD and type 2 DM [20]; thereafter, pharmacological strategy could be considered.

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5.1.2

Insulin-sensitizing drugs

Metformin, alone or combined with other drugs, offers metabolic benefit in preventing type 2 DM and CVD. In PCOS women, metformin improves insulin resistance index, prevents impaired glucose tolerance (IGT) and type 2 DM, and reduces the conversion of IGT in diabetes; however to date, its prophylactic administration is not recommended in this population of women [20]. Compared with COCs, metformin is more effective in reducing fasting insulin, without difference in fasting glucose levels [137]. The metformin monotherapy performs a beneficial effect on arterial pressure, by improving vascular function [222]. Similarly, in young PCOS women 6-month course of metformin-DRSP/ EE2 30 µg that induced a reduction of endothelial dysfunction was observed [223] along with a decrease of aortic elastic parameters (stiffness index, distensibility and strain) [224]. Finally, the biguanide prevents and controls dyslipidemia, common condition in obese and non-obese PCOS women [225], by reducing triglycerides and low-density lipoprotein (LDL) cholesterol and increasing high-density lipoprotein (HDL) [183,225]. Other drugs The use of spironolactone prevents CV complications through androgens and renin--angiotensin--aldosterone system, which are involved in the atherogenic process in PCOS women. Antiandrogens, in non-obese PCOS patients, normalize endothelial function and improve cholesterol levels; however, further studies are necessary to confirm these preliminary results [226]. Statins (atorvastatin, simvastatin) induce CV benefit in PCOS patients by improving chronic inflammation and lipid profile, hyperandrogenemia, oxidative stress and metabolic parameters [227]. Notwithstanding these interesting results, several adverse events (impairment of insulin sensitivity after atorvastatin, myopathy and renal impairment, teratogenic complication) limit their use, thus lipid-lowering agents should be used in women who satisfy the indications for treatment (LDL > 160 mg/dl; non-HDL ‡ 190m g/dl) [11] and the therapy should start according to individual risk for CVD. Orlistat, an anti-obesity drug, combined with lifestyle changes induces substantial weight loss in women with PCOS, resulting in improvement in insulin resistance and CV risk factors [116]; however, it is not recommended given the poor clinical experience related to its use [47]. 5.1.3

5.2

Oncologic complications Definition and diagnosis

5.2.1

PCOS women are exposed to a risk of developing EC of 20 -- 37% [228], three times higher than healthy women [229], while the prevalence of endometrial hyperplasia (EH) varies from 1 to 48.8%, with a wide range that probably reflects the heterogeneous nature of the PCOS phenotype and diagnostic criteria adopted [228]. 1382

The identified pathogenetic pathways seem to be linked to insulin resistance and chronic anovulation, thus several strategies in PCOS women aim to treat risk factors for EC (such as obesity and anovulation). Hormonal therapy Progestogens represent efficacious, low costs and welltolerated drugs adopted in prevention and treatment of EH/ EC in PCOS women. The induction of regular withdrawal bleeding with progestogens in obese amenorrheic PCOS women optimally prevents EH; similarly, EC risk decreases by inducing a withdrawal bleed every 3 -- 4 months with progestins [230]. There is no standardized guideline to manage EH in PCOS patients; clinical strategies depend on age, fertility concerns and histology [228]. In young women, progestin represents an optimal conservative treatment in order to preserve the integrity of reproducing system [231]; furthermore, their side effects limit patient’s compliance. Cyclic progestin inhibits endometrial proliferation, but induces persistency or progression of atypical EH in 26.9% of women [231], with a relapse rate of 14 -- 30% [232]. Levonorgestrel-releasing intrauterine system (LNG-IUS) is an effective, safe, non-surgical and atraumatic approach with few side effects (abnormal bleeding patterns in 50 -- 89% of users) [233] for the treatment of EH in PCOS patients, inducing a significant reduction in endometrial thickness after 12 months [234] with complete disappearance of simple and irregular cases of EH and a decreased number of complex EH. Recently, Stanosz et al. [235] have assessed a combined treatment (transdermal hormonal replacement therapy, metformin, bromocriptine mesylate and melatonin) for preinvasive EC (IA/G1) in young women with PCOS, showing that this approach favorably influences concentrations of female sexual hormones, lipid metabolism and causes the restoration of normal endometrium. 5.2.2

Insulin-sensitizing drugs Metformin might be a pharmacological approach to prevent or treat EH/EC, since its insulin-sensitizing actions (weight loss, menstrual cyclicity, reduction of T levels and aromatase activity) reduce mitogen mechanism on uterine cells [236]. The biguanide increases P receptor expression and plays an anti-proliferative effect by inhibiting the mammalian target of rapamycin [237,238]. Few data are available about the effective efficacy of metformin in the treatment of EH in PCOS women [239-241], thus further controlled study should be performed. 5.2.3

6.

Conclusion

COCs are the first-line management in PCOS women presenting with mild or moderate/severe hirsutism and/or menstrual abnormalities who not desire pregnancy. EPs and

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antiandrogens are equally efficacious in reducing hirsutism, thus the choice depends on patients’ desire and costs. Each treatment should be prescribed for at least 6 months before changing the dose, type of drug or therapeutic scheme. CC is the gold standard in ovulation induction protocol. Metformin may have benefit as adjuvant agent in obese infertile women, but cannot be considered as a first-line agent [11]. The combination metformin plus clomiphene represents the most effective strategy in CC resistance. Further trials are necessary to confirm the role of AIs in both first-line drug and in CC-resistant women. Low-dose gonadotropin protocol represents an efficacious third-line strategy for mono-ovulation induction [136]; and the GnRH antagonist protocol is effective and safer than long GnRH agonist protocol in women with PCOS undergoing IVF/ICSI treatment. Moreover, to reduce OHSS risk in IVF cycle, clinicians have two alternatives to trigger oocyte: i) maturation with a bolus of GnRH agonist and supplement the luteal phase with a small bolus of hCG and more intensive estradiol and P supplementation; ii) GnRH agonist administration and subsequent freezing of blastocysts [207]. All PCOS women should be screened for CVD risk factors (family history of early CVD, smoke, IGT)/type 2 DM, hypertension, dyslipidemia, obesity), and should be invited to change their lifestyle. Metformin is an efficient therapy in preventing CV complications and DM, but today no recommendations about its employment is provided. Since no standardized guidelines for the management of EH/EC in PCOS women are available, the induction of regular menstrual withdrawal bleeding with progestogens is an optimal prevention strategy; in particular, LNG-IUS is an efficient device to treat hyperplasia [234]. As far as the metformin employment in prevention and cure of EC is concerned, even if we take into consideration experimental data already published, further clinical trials on PCOS subjects are needed. 7.

Expert opinion

Differently from to other pathologies, in PCOS patients a common denominator of the various pharmacological treatments does not exist. Clinicians should exert before treatment an accurate evaluation of patients’ characteristics, identifying the phenotypic target and the best-tailored treatment. Furthermore, given the variety of phenotype of PCOS women, each pharmacological treatment could be tailored to one or more clinical issues, in relation to the reproductive desire. Thus, hyperandrogenism and menstrual disorders should be treated independently from infertility, knowing that EPs, progestins and antiandrogens negatively affect reproductive outcomes. The first-line treatment for PCOS patients should be nonpharmacological (weight loss and lifestyle modifications), since it improves metabolic and menstrual outcomes [12]. This is the first advice that every gynecologist should give to

PCOS patient, and should inform the woman that this approach is often more important than any drug. Thereafter, the reproductive desire of the woman should be investigated in order to start the most suitable and rapid way to get the results. In young PCOS girls, without immediate desire for pregnancy, hormonal therapy (COCs, antiandrogen) is the firstline treatment of mild and moderate/severe hirsutism and/or menstrual abnormalities. Since EPs and antiandrogens are equally efficacious in reducing hirsutism, the choice depends on the patients’ desire, effects and costs [11,20], remembering that they might be eventually associated. In PCOS women, progestogens prevent EH/EC; similarly LNG-IUS is effective for the treatment of EH [234]. The treatment changes in presence of women looking for pregnancy. In this context, we have to advice our patients that PCOS is not an absolute cause of infertility, but restoring ovulation is not always simple, and sometimes, repeated attempts are needed, given the high rates of cycle cancellations due to multiple follicular recruitment. If time intercourse or IUI is scheduled, CC represents the first-line strategy [136] in ovulation induction protocol; compared with CC, AIs seem to obtain the same reproductive outcomes, but further data are necessary and its being off-label significantly limits their use. If we could show that letrozole is equally effective in restoring ovulation but with less negative effects on the quality of the endometrium compared with clomiphene, probably the AIs would become the new first-line drugs for single ovulation induction. Low-dose therapy with gonadotropins offers a high rate of ovulation and monofollicular development, but especially in women with very high level of anti-Mu¨llerian hormone (AMH) or with OvAge (a numeric variable which accurately reflects the ovarian reserve, gotten by a mathematical formula which accounts patient’s biochemical [FSH, E2, AMH] and ultrasonographic [Antral Follicle Count, ovarian volume, Flow index, Vascularization Index and Vascularization Flow Index] parameters as predictor variables) significantly lower than chronological age [242], repeated stimulation are needed for finding the right starting dose, being these PCOS women very resistant to the low doses suggested by guidelines. In this scenario, clinician managing PCOS infertile women should be confident with the new stimulation protocols available for high-responders and should be able to offer good prognosis IVF cycles in modern and qualified laboratories, able to ensure high success rates in cycles with thawed blastocyst. In IVF settings, indeed, considering the high risk of OHSS in PCOS women, GnRH antagonist protocols with GnRH agonist for ovulation triggering followed by a freeze-all of blastocysts strategy is the best method to completely avoid OHSS in PCOS women [207]. Young PCOS women with good ovarian reserve, after 3 -- 6 cancelled cycles of time intercourse or IUI, in presence of some degree of male factor, could then benefit of a rapid IVF attempts, given the high

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rate of pregnancy and live-birth with no more risks related to hyper-response. At any stage of a PCOS woman’s reproductive life, metformin represents an efficacious and safe choice. It has pleiotropic -sensitizing actions [243] through which improves fasting and glucose-stimulated insulin, reduces ovarian androgen production [244] and circulating androgen [95,138]. Interestingly, a recent study shows that it induces a prompt decrease in LH-stimulated T secretion after only few days of use, preceding the medication’s effects on insulin sensitivity or weight loss [245]. Unfortunately, metformin is still an off-label drug not approved by the US FDA for PCOS treatment, notwithstanding a well-recognized clinical efficacy since 1994 [246]. Metformin is not a first-line treatment for dermatological issues and menstrual abnormalities in PCOS patients even if it might be considered in women desiring pregnancy [11,107], particularly in obese ones, being an effective therapy in preventing CV complications and DM. Future studies, aimed to determine the optimal metformin dosage and regimens in relation to women’s characteristics (age, BMI, insulin resistance state) are needed, again in order to define a specific approach, tailored on any kind of PCOS patients. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

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Affiliation Morena Luigia Rocca MD, Roberta Venturella MD, Rita Mocciaro† MD, Annalisa Di Cello MD, Angela Sacchinelli MD, Valentina Russo MD, Simona Trapasso MD, Fulvio Zullo PhD & Michele Morelli PhD † Author for correspondence ‘Magna Graecia’ University, Cancer Center of Excellence “Tommaso Campanella” of Germaneto, Department of Experimental and Clinical Medicine, Unit of Obstetrics and Gynaecology, Oncology Unit, Viale Europa, loc. Germaneto, 88100, Catanzaro, Italy Tel: +39 328 5692428; Fax: +39 0961 883234; E-mail: [email protected]

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Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disease among women of childbearing age. The clinical features are heteroge...
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