Introduction

Epidemiology

In women, polycystic ovary syndrome (PCOS) is a common endocrine/ metabolic disorder. Its prevalence depends on the diagnostic criteria used since each criterion includes various PCOS phenotypes.

In a 2016 meta-analysis of 24 population studies performed in Europe, Australia, Asia, and the United States, the rates of PCOS (and 95% confidence interval) according to diagnostic criteria in unselected populations were [1].

1. The National Institutes of Health (NIH) – 6 per cent (5 to 8 per cent, n = 18 trials)
2. Rotterdam criteria – 10 per cent (8 to 13 per cent, n = 15 trials)
3. Androgen Excess and PCOS (AE-PCOS) Society criteria – 10 per cent (7 to 13 per cent, n = 10 trials)

Therefore, the estimate prevalence of PCOS is approximately 6 per cent, but the actual prevalence probably closer to 10 per cent of reproductive-age women. Although the disorder is primarily heritable, this prevalence likely translates to the entire female population, regardless of age [2].

Phenotypes of PCOS

1. Phenotype A "full PCOS" includes biochemical or clinical hyperandrogenism, oligo ovulation, and polycystic ovarian morphology
2. Phenotype B "classic PCOS" includes hyperandrogenism and oligo anovulation
3. Phenotype C "ovulatory PCOS" includes hyperandrogenism and polycystic ovarian morphology
4. Phenotype D "non-hyperandrogenic PCOS" includes oligo anovulation and polycystic ovarian morphology

The NIH criteria include only phenotypes A and B, the AE-PCOS Society criteria for phenotypes A, B, and C, and the Rotterdam criteria for all four phenotypes. These criteria, with minor adjustments, have been reaffirmed by a recent international evidence-based guideline for the assessment and management of PCOS[3].

Pathogenesis

In their original report[4], Stein and Leventhal emphasized the dyad of what they called "polycystic" ovaries in association with amenorrhea. Although they also noted that some of their subjects had hirsutism or acne, these features were not as central to the syndrome. They observed that "bilateral polycystic ovaries are most probably a result of some hormonal stimulation and very likely relate to the anterior lobe of the pituitary gland" [5].

Genetics: PCOS is a complex genetic trait similar to cardiovascular disease, type 2 diabetes mellitus, and metabolic syndrome, where multiple genetic variants and environmental factors interact to foster the development and features of the disorder[6-8].

Altered LH: PCOS patients often have higher serum LH concentrations[9,10] and increased LH pulse frequency and amplitude [11] than matched controls. However, serum LH tends to be lower in obese women with PCOS compared with their lean counterparts [12,13].

Insulin secretion and action: Insulin resistance, and the development of compensatory hyperinsulinemia, is a frequent finding in PCOS [14-20].

Obesity and energy regulation: The presence of obesity worsens insulin resistance, the degree of hyperinsulinemia, the severity of ovulatory and menstrual dysfunction, and pregnancy outcome in PCOS and is associated with an increasing prevalence of metabolic syndrome, glucose intolerance, cardiovascular risk factors, and sleep apnea [21- 25].

Androgen biosynthesis and action:Hyperandrogenism is a central feature for most forms (phenotypes A through C) of PCOS. The androgens are secreted primarily by the ovaries and secondarily by the adrenals [26].

Environmental factors: The most clearly defined environmental factor likely affecting the development of PCOS is diet and its association with Obesity, despite wide variations in the prevalence of Obesity and type of diet [27]. The prevalence of PCOS appears to be relatively uniform across the globe [1,28-31].

Risk factors for PCOS

Many risk factors were proven to increase the risk of PCOs, such as:

1. Oligoovulatory infertility [32-34], Obesity [35-39] and insulin resistance [40,41].
2. Type 1, type 2, or gestational diabetes mellitus [42-47].
3. A history of premature adrenarche [48]
4. First-degree relatives with PCOS [49]
5. Antiseizure medications –mainly valproate [50-51].

Diagnosis

Clinical features Of PCOS

Menstrual dysfunction: Menstrual irregularity typically begins in the peripubertal period and may be delayed menarche. The menstrual pattern is typically either oligomenorrhea or amenorrhea.

Hyperandrogenism: (hirsutism, acne, male-pattern hair loss) associated with or without elevated serum androgen concentrations.

Polycystic ovaries: The typical polycystic appearance of the ovaries on transvaginal ultrasound (TVUS) in most women with irregular menses and hyperandrogenism. However, this ultrasound appearance is nonspecific as it may also present in normal-cycling women.

Diagnostic criteria

Rotterdam criteria: Most expert groups use Rotterdam criteria to make the diagnosis of PCOS [52-55], two out of three of the following criteria are required to make the diagnosis [56]

1. Oligo- and/or anovulation
2. Clinical and/or biochemical signs of hyperandrogenism
3. Polycystic ovaries (by ultrasound).
4. In 1990, the National Institutes of Health (the NIH criteria) allowed for a clinical diagnosis without using an imaging In addition, the NIH criteria require the presence of irregular menses, while the other criteria do not [57].
5. In 2006, the Androgen Excess (AE) and PCOS Society proposed the AE-PCOS Criteria [58]In contrast to the Rotterdam criteria, the majority of the AE-PCOS task force agreed that there were insufficient data to define women with ovulatory dysfunction and polycystic ovaries, but no evidence of hyperandrogenism, as having PCOS [58].

Differential Diagnosis

The diagnosis of PCOS is confirmed once other conditions with features similar to PCOS have been excluded, such as non-classic congenital adrenal hyperplasia (NCCAH), thyroid disease, and hyperprolactinemia. Women with severe hyperandrogenism and virilization require a more extensive evaluation for the most serious causes of androgen excess (androgen-secreting ovarian and adrenal tumors and ovarian hyperthecosis) [55].

Nonclassic congenital adrenal hyperplasia (NCCAH) is less common than PCOS but should be ruled out because there are risks that offspring could be affected with the more severe classic 21-hydroxylase deficiency.Testing for NCCAH deficiency by measuring 17-hydroxyprogesterone at 8 AM. This test is most important in high-risk women, including Mediterranean, Hispanic, and Ashkenazi Jewish women.

A. Androgen-secreting tumors/ovarian hyperthecosis

Present with recent onset of severe hirsutism, sudden progressive worsening of hirsutism, and symptoms or signs of virilization, including frontal balding, severe acne, clitoromegaly, increased muscle mass or deepening of the voice.

Their serum testosterone concentrations are almost always greater than 150 ng/dL (5.2 nmol/L) [59], and those with adrenal tumors typically have serum dehydroepiandrosterone sulfate (DHEAS) concentrations higher than 800 mcg/dL (21.6 micromol/L).

Oligomenorrhea can be seen with hypothyroidism, hyperthyroidism, and hyperprolactinemia. These disorders are distinguished by their clinical features and biochemical testing (high TSH, low TSH, high prolactin).

Common Comorbidities

Cardiovascular

There is a high prevalence of obesity and insulin resistance among women with PCOS; they are at increased risk for type 2 diabetes, dyslipidemia, and Coronary Heart Disease (CHD).

Several professional organizations, including the American College of Obstetricians and Gynecologists (ACOG), the American Association of Clinical Endocrinologists (AACE) [60].the Androgen Excess Society [61], and a consensus panel representing the European Society of Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM) [56]. suggest the following assessments:

1. Blood pressure and body mass index (BMI) at initial diagnosis and after that. Waist circumference should also be measured.
2. Fasting lipid profile at initial
3. A two-hour oral glucose tolerance test (OGTT) (with measurement of fasting and two-hour glucose) in all women with PCOS at initial If this is not feasible, fasting glucose should be obtained by measuring the glycatedhaemoglobin (A1C) concentration.

Furthermore, the Androgen Excess Society also suggest the following [61]:

1. Patients with standard glucose tolerance should be rescreened at least once every two years or more frequently if additional risk factors are identified.
2. Patients with impaired glucose tolerance should be screened annually for the development of type 2

Sleep apnea

women with PCOS should be questioned about the signs and symptoms of sleep apnea (snoring, excessive daytime sleepiness, and morning headaches). If signs and symptoms suggest the diagnosis, the patient should be referred to a sleep medicine clinician

Anovulatory infertility

Transvaginal ultrasound (TVUS): monitors follicular growth and number in those with anovulatory infertility undergoing ovulation induction.

Nonalcoholic fatty liver disease

Although women with PCOS appear to be at increased risk for nonalcoholic fatty liver disease (NAFLD),. Current guidelines do not recommend screening for any groups at high risk for this disorder[62].

Depression and anxiety disorders

Women with PCOS may be more likely to have mood disorders (depression and anxiety) than women with similar BMI without PCOS. They are also at risk for eating disorders (binge eating). Several expert societies suggest screening all women with PCOS for depression and anxiety [52-55]. The best approach is to use brief, validated screening tools such as the Patient Health Questionnaire (PHQ-9) for depression and the Generalized Anxiety Disorder 7 (GAD-7) anxiety scale for anxiety disorders.

Management Menstrual irregularities

The chronic anovulation seen in PCOS is associated with an increased risk of endometrial hyperplasia and possibly endometrial cancer.

First-line therapy for menstrual dysfunction and endometrial protection is combined estrogen-progestin oral contraceptives (COCs) [52,55]. The absence of pregnancy should be confirmed before initiating COCs.

COCs benefit women with PCOS, including:

1) Daily exposure to progestin, which antagonizes the

endometrial proliferative effect of estrogen.

2) Contraception, as women with oligomenorrhea ovulate intermittently and unwanted pregnancy may occur.

3) Cutaneous benefits for hyperandrogenic manifestations.

Alternative treatments for endometrial protection are intermittent or continuous progestin therapy or a progestin- releasing intrauterine device (IUD) [63].

Medroxyprogesterone acetate (5 to 10 mg) for 10 to 14 days every one to two months. Progestin therapy alone will not reduce the symptoms of acne or hirsutism, nor will it provide contraception. However, continuous progestin therapy with norethisterone 0.35 mg daily provides contraception and endometrial protection.

Metformin is a potential alternative to restore menstrual cycles as it restores ovulatory menses in approximately 30 to 50 percent of women with PCOS [64,65]. However, Its ability to provide endometrial protection is less well established, so consider it second-line therapy [66,67].

Hirsutism

The Endocrine Society Clinical Practice Guidelines 2018 on Hirsutism suggest a COC as first-line pharmacologic therapy for most women [68]. In addition, both the Endocrine Society Clinical Practice Guidelines on the Diagnosis and Treatment of Polycystic Ovary Syndrome and international guidelines for assessing and managing PCOS [55] suggest COCs as first-line therapy for hirsutism [52]. After six months, if the patient is not satisfied with the clinical response to COC monotherapy (for hyperandrogenic symptoms), we typically add spironolactone 50 to 100 mg twice daily.

Hirsutism can also be treated by removal of hair by mechanical means such as shaving, waxing, depilatories, electrolysis, or laser treatment. In addition, eflornithine hydrochloride cream (13.9%) is a topical drug that inhibits hair growth. It is not a depilatory and must be used indefinitely to prevent regrowth [68].

Metabolic abnormalities

Obesity

Weight loss, which can restore ovulatory cycles and improve metabolic risk, is the first-line intervention for most women. The approach to obesity management is the same as that for patients without PCOS, starting with lifestyle changes (diet and exercise) [69], followed by pharmacotherapy and, when necessary, bariatric surgery

Weight reduction

They suggest weight-loss strategies using calorie- restricted diets combined with exercise for women with PCOS and obesity. Although there are no large randomized trials of exercise-specific interventions, a systematic review of exercise therapy in PCOS concluded that there may be modest weight loss and improvements in ovulation and insulin sensitivity [70]. Even modest weight loss (5 to 10 percent reduction in body weight) in women with PCOS may result in the restoration of regular ovulatory cycles [71-73] and improved pregnancy rates [74]in short-term studies.

Insulin resistance/type 2 diabetes

Several drugs, including biguanides( metformin) and thiazolidinediones (pioglitazone, rosiglitazone), can reduce insulin levels in women with PCOS. These drugs may also reduce ovarian androgen production (and serum-free testosterone concentrations) and restore normal menstrual cyclicity [75-78].

Dyslipidemia

The approach to the treatment of dyslipidemia in women with PCOS is the same as for other patients with dyslipidemia. Exercise and weight loss are the first-line approaches, followed by pharmacotherapy. Statin therapy decreased serum low-density lipoprotein (LDL) and triglycerides but did not affect high-density lipoprotein (HDL), fasting insulin, or C-reactive protein. A slight decrease in serum testosterone was observed, but there were no improvements in menstrual cycle regularity, ovulation, acne, hirsutism, or BMI [79].

Obstructive sleep apnea

Sleep apnea, a common disorder in women with PCOS, is an essential determinant of insulin resistance, glucose intolerance, and type 2 diabetes. Obstructive sleep apnea, treatment with continuous positive airway pressure (CPAP) improved insulin sensitivity and reduced diastolic blood pressure [80]. A similar benefit was reported in a meta- analysis of eight studies [81].

Nonalcoholic steatohepatitis

The prevalence of nonalcoholic steatohepatitis (NASH) appears to be increased in women with PCOS. Both weight loss and metformin use appear to improve metabolic and hepatic function in these women [82,83].

Depression/anxiety

There is evidence that women with PCOS have impaired quality of life and higher rates of depression and anxiety when compared with women of similar BMI without PCOS [84]. However, the efficacy and safety of antidepressant therapy has not yet been established in women with PCOS and anxiety or depression [85].

Anovulation and Infertility

Weight loss

The approach to obesity management is the same as that for patients without PCOS, starting with lifestyle changes (diet and exercise) [69] and bariatric surgery if necessary[86].

Ovulation induction medications:

For oligo-ovulatory women with PCOS undergoing ovulation induction, letrozole is first-line therapy over clomiphene citrate, regardless of the patient's BMI. the drug is not approved by the US Food and Drug Administration (FDA) for this purpose, Therefore, Clomiphene citrate had been the first-line drug for this population for many years, with metformin as an alternative. However, clomiphene and metformin appear less effective for live birth rates than letrozole [87].

1. Gonadotropin therapy is the administration of exogenous gonadotropins [88]. Women with PCOS and anovulatory infertility treated with gonadotropins are at high risk for ovarian hyper stimulation syndrome (OHSS).
2. In vitro fertilization (IVF) If the over mentioned strategies fail, the next step is IVF, however, the risk of OHSS is high in women with PCOS undergoing controlled ovarian hyperstimulation for IVF, and metformin administration before or during IVF cycles may reduce this risk [89-91].

References

1. Bozdag G, Mumusoglu S, Zengin D, et The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Human Reproduction31(2016): 2841-2855.
2. Vink JM, SadrzadehS, Lambalk CB,et Heritability of Polycystic Ovary Syndrome in a Dutch Twin- Family Study. The Journal of Clinical Endocrinology & Metabolism91 (2006): 2100-2104.
3. Teede HJ, Misso ML, Costello MF, et Erratum. Recommendations from the international evidence- based guideline for the assessment and management of polycystic ovary syndrome. Human Reproduction 34 (2018): 388-388.
4. Stein IF,Leventhal Amenorrhea associated with bilateral polycystic ovaries. American Journal of Obstetrics and Gynecology29 (1935): 181-191.
5. Geist Reaction of the mature human ovary to antuitrin-s. American Journal of Obstetrics and Gynecology26 (1933): 588-592.
6. Vink JM, Sadrzadeh S, Lambalk CB, et Heritability of Polycystic Ovary Syndrome in a Dutch Twin- Family Study. The Journal of Clinical Endocrinology & Metabolism91 (2006): 2100-2104.
7. Legro RS, Driscoll D, Strauss JF, et Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proceedings of the National Academy of Sciences of the United States of America, [online] 95(1998): 14956-14960.
8. Kahsar-Miller MD, Nixon C, Boots LR, et al. Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertility and Sterility75 (2001): 53-58.
9. Rebar R, Judd HL, Yen SS, et al. Characterization of the inappropriate gonadotropin secretion in polycystic ovary Journal of Clinical Investigation 57 (1976): 1320-1329.
10. Balen Hypersecretion of luteinizing hormone and the polycystic ovary syndrome. Human Reproduction 8(1993): 123-128.
11. Waldstreicher J, Santoro NF, Hall JE, et Hyperfunction of the Hypothalamic-Pituitary Axis in Women with Polycystic Ovarian Disease: Indirect Evidence for Partial Gonadotroph Desensitization*. The Journal of Clinical Endocrinology & Metabolism 66 (1988): 165-172.
12. Taylor AE, McCourt B, Martin KA, et Determinants of Abnormal Gonadotropin Secretion in Clinically Defined Women with Polycystic Ovary Syndrome1. The Journal of Clinical Endocrinology & Metabolism 82 (1997): 2248-2256.
13. Jakimiuk Luteinizing Hormone Receptor, Steroidogenesis Acute Regulatory Protein, and Steroidogenic Enzyme Messenger Ribonucleic Acids Are Overexpressed in Thecal and Granulosa Cells from Polycystic Ovaries. Journal of Clinical Endocrinology & Metabolism86(2001): 1318-1323.
14. Burghen GA, Givens JR,Kitabchi Correlation of Hyperandrogenism with Hyperinsulinism in Polycystic Ovarian Disease*. The Journal of Clinical Endocrinology & Metabolism 50(1980): 113-116.
15. Carmina E, Koyama T, Chang L, et al. Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance   in   polycystic   ovary syndrome? International Journal of Gynecology & Obstetrics 42(1993): 224-224.
16. Dunaif Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis1. Endocrine Reviews18 (1997): 774-800.
17. Legro RS, Finegood D,Dunaif A. A Fasting Glucose to Insulin Ratio Is a Useful Measure of Insulin Sensitivity in Women with Polycystic Ovary Syndrome1. The Journal of Clinical Endocrinology & Metabolism83(1998): 2694-
18. DeUgarte CM, Bartolucci AA,Azziz R. Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertility and sterility83(2005): 1454-1460.
19. Brower M, Brennan K, Pall M,et al. The Severity of Menstrual Dysfunction as a Predictor of Insulin Resistance in The Journal of Clinical Endocrinology & Metabolism98(2013): E1967–E1971.
20. Landay M, Huang A,Azziz Degree of hyperinsulinemia,independent of androgen levels, is an important determinant of the severity of hirsutism in PCOS. Fertility and Sterility92(2009): 643-647.
21. Legro RS, Kunselman AR, Dodson WC,et al. Prevalence and Predictors of Risk for Type 2 Diabetes Mellitus and Impaired Glucose Tolerance in Polycystic Ovary Syndrome: A Prospective, Controlled Study in 254 Affected Women1. The Journal of Clinical Endocrinology & Metabolism, 84(1999): 165-169.
22. Ehrmann DA, Liljenquist DR, Kasza K, et al. Prevalence and Predictors of the Metabolic Syndrome in Women with Polycystic Ovary The Journal of Clinical Endocrinology & Metabolism 91(2006): 48-53.
23. Obesity and insulin resistance but not hyperandrogenism mediates vascular dysfunction in women with polycystic ovary syndrome. Fertility and Sterility86(2066): 1702-
24. Barber TM, McCarthy MI, Wass JAH, et    Obesity and polycystic ovary syndrome. Clinical Endocrinology65(2006): 137-145.
25. Boomsma CM, Eijkemans MJC, Hughes EG, et al. A meta-analysis of pregnancy outcomes in women with polycystic ovary Human Reproduction Update12(2006): 673-683.
26. Kumar A, Woods KS, Bartolucci AA,et al. Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). Clinical Endocrinology62(2005): 644-649.
27. Carmina Difference in body weight between American and Italian women with polycystic ovary syndrome: influence of the diet. Human Reproduction, 18 (2003): 2289-2293.
28. Azziz R, Woods KS, Reyna R, et The Prevalence and Features of the Polycystic Ovary Syndrome in an Unselected Population. The Journal of Clinical Endocrinology &Metabolism 89(2004): 2745-2749.
29. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, et al. A Survey of the Polycystic Ovary Syndrome in the Greek Island of Lesbos: Hormonal and Metabolic Profile. The Journal of Clinical Endocrinology & Metabolism 84(1999): 4006-4011.
30. Asunción M, Calvo RM, San Millán JL, et A Prospective Study of the Prevalence of the Polycystic Ovary Syndrome in Unselected Caucasian Women from Spain1. The Journal of Clinical Endocrinology & Metabolism 85(2000): 2434-2438.
31. Michelmore KF, BalenAH, Dunger DB, et al. Polycystic ovaries and associated clinical and biochemical features in young Clinical Endocrinology51(1999): 779-786.
32. Broekmans F, Knauff E, Valkenburg O, et PCOS according to the Rotterdam consensus criteria: change in prevalence among WHO-II anovulation and association with metabolic factors. BJOG: An International Journal of Obstetrics &Gynaecology113(2006): 1210-1217.
33. Kousta E, White DM, Cela E, et al. The prevalence of polycystic ovaries in women with Human Reproduction14(1999): 2720-2723.
34. Allen SE, Downing Potter H,Azziz Prevalence of hyperandrogenemia among nonhirsuteoligo-ovulatory women. Fertility and Sterility 67(1997): 569-572.
35. Álvarez-Blasco F, Botella-Carretero JI, San Millán JL, et Prevalence and Characteristics of the Polycystic Ovary Syndrome in Overweight and Obese Women. Archives of Internal Medicine166(2006): 2081.
36. Yildiz BO, Knochenhauer ES,Azziz Impact of Obesity on the Risk for Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology & Metabolism 93 (2008): 162-168.
37. Azziz R, Sanchez LA, Knochenhauer ES, et Androgen Excess in Women: Experience with Over 1000 Consecutive Patients. The Journal of Clinical Endocrinology & Metabolism 89(2004): 453-462.
38. Hedley Prevalence of Overweight and Obesity Among US Children, Adolescents, and Adults, 1999- 2002. JAMA291(2004): 2847.
39. Carmina E, Rosato F, Jannì A, et al. Relative Prevalence of Different Androgen Excess Disorders in 950 Women Referred because of Clinical The Journal of Clinical Endocrinology & Metabolism, 91(2006): 2-6.
40. Hartz AJ, Barboriak PN, Wong A, et The association of obesity with infertility and related menstural abnormalities in women. International Journal of Obesity3(1979): 57-73.
41. Korhonen S, Hippeläinen M, Niskanen L, et Relationship of the metabolic syndrome and obesity to polycystic ovary syndrome: A controlled, population- based study. American Journal of Obstetrics and Gynecology 184 (2001): 289-296.
42. Escobar-Morreale HF, Roldán B, Barrio R, et al. High prevalence of the polycystic ovary syndrome and hirsutism in women with type 1 diabetes mellitus. The Journal of Clinical Endocrinology and Metabolism, [online] 85(2000): 4182-4187.
43. Codner E, Soto N, Lopez P, et al. Diagnostic Criteria for Polycystic Ovary Syndrome and Ovarian Morphology in Women with Type 1 Diabetes Mellitus. The Journal of Clinical Endocrinology & Metabolism 91(2006): 2250-
44. Peppard HR, MarforiJ, Iuorno MJ,et al. Prevalence of Polycystic Ovary Syndrome Among Premenopausal Women With Type 2 Diabetes. Diabetes Care24 (2001): 1050-1052.
45. Holte J, Gennarelli G, Wide L, et al. High Prevalence of Polycystic Ovaries and Associated Clinical, Endocrine, and Metabolic Features in Women with Previous Gestational Diabetes Mellitus. The Journal of Clinical Endocrinology & Metabolism83(1998): 1143-1150.
46. Anttila Polycystic Ovaries in Women With Gestational Diabetes. Obstetrics & Gynecology 92(1998): 13-16.
47. Conn JJ, Jacobs HS,Conway The prevalence of polycystic ovaries in women with type 2 diabetes mellitus. Clinical Endocrinology 52(2000): 81-86.
48. Rosenfield RL. Identifying Children at Risk for Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology & Metabolism92(2007): 787-796.
49. Kahsar-Miller MD, Nixon C, Boots LR, et al. Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS. Fertility and Sterility 75 (2001): 53-58.
50. Isojärvi JI, Laatikainen TJ, Pakarinen AJ, et Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. The New England Journal of Medicine329 (1993): 1383-1388.
51. Mikkonen K, Vainionpää LK, Pakarinen AJ, et al. Long- term reproductive endocrine health in young women with epilepsy during Neurology 62 (2004): 445-450.
52. Teede HJ, Misso ML, Costello MF, et Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertility and Sterility 110 (2018): 364-379.
53. Alsamarai S, Adams JM, Murphy MK, et al. (2009). Criteria for Polycystic Ovarian Morphology in Polycystic Ovary Syndrome as a Function of Age. The Journal of Clinical Endocrinology & Metabolism 94 (2009): 4961-
54. Azziz Defining what is normal: the key to the diagnosis of polycystic ovary syndrome (and any other disorder for that matter…). Fertility and Sterility 111 (2019): 681-682.
55. Legro RS, Arslanian SA, Ehrmann DA, et al. (2013). Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism 98 (2013): 4565-4592.
56. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human Reproduction 19 (2004): 41-47.
57. Zawadski JK, Dunaif Diagnostic criteria for polycystic ovary syndrome: Towards a rational approach. In: Polycystic Ovary Syndrome (Current Issues in Endocrinology and Metabolism), Dunaif A, Givens JR, Haseltine FP, Merriam GE (Eds), Blackwell Scientific Inc., Boston (1992): 377.
58. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertility and Sterility 91 (2009): 456-488.
59. Derksen J, Nagesser SK, Meinders AE, et al. Identification of Virilizing Adrenal Tumors in Hirsute Women. New England Journal of Medicine 331 (1994): 968-973.
60. Cobin R, Futterweit W, Nestler J, et American Association of Clinical Endocrinologists Position Statement on Metabolic and Cardiovascular Consequences of Polycystic Ovary Syndrome. Endocrine Practice 11 (2005): 125-134.
61. Salley KES, Wickham EP, Cheang KI, et al. POSITION STATEMENT: Glucose Intolerance in Polycystic Ovary Syndrome—A Position Statement of the Androgen Excess Society. The Journal of Clinical Endocrinology & Metabolism 92 (2007): 4546-4556.
62. Makri E, Tziomalos Prevalence, etiology and management of non-alcoholic fatty liver disease in patients with polycystic ovary syndrome. Minerva Endocrinology 42(2017).
63. Dumesic DA,Lobo RA. Cancer risk and PCOS. Steroids, [online] 78 (2013): 782-785.
64. Moghetti P, Castello R, Negri C, et al. Metformin Effects on Clinical Features, Endocrine and Metabolic Profiles, and Insulin Sensitivity in Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled 6-Month Trial, followed by Open, Long-Term Clinical The Journal of Clinical Endocrinology & Metabolism 85 (2000): 139-146.
65. Unluhizarci K, Kelestimur F, Bayram F, et The effects of metformin on insulin resistance and ovarian steroidogenesis in women with polycystic ovary syndrome. Clinical Endocrinology 51 (1999): 231-236.
66. Legro RS, Zaino RJ, Demers LM, et al. The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary American Journal of Obstetrics and Gynecology 196 (2007): 402.e1–402.e11.
67. Tang T, Lord JM, Norman RJ, et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligoamenorrhoea and subfertility. Cochrane Database of Systematic Reviews (2012).
68. Martin KA, Anderson RR, Chang RJ, et al. Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society* Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism 103 (2018): 1233-1257.
69. Pasquali R, Gambineri A, Cavazza C, et Heterogeneity in the responsiveness to long-term lifestyle intervention and predictability in obese women with polycystic ovary syndrome. European Journal of Endocrinology 164 (2011): 53-60.
70. Harrison CL, Lombard CB, Moran LJ,et Exercise therapy in polycystic ovary syndrome: a systematic review. Human Reproduction Update 17 (2010): 171-183.
71. Pasquali R, Antenucci D, Casimirri F,   et    Clinical and Hormonal Characteristics of Obese AmenorrheicHyperandrogenic Women before and After Weight Loss*. The Journal of Clinical Endocrinology & Metabolism 68 (1989): 173-179.
72. Kiddy DS, Hamilton-Fairley D, Bush A, et Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clinical Endocrinology 36 (1992): 105-111.
73. Huber-Buchholz MM, Carey DG, Norman Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. The Journal of clinical endocrinology and metabolism 84 (1999): 1470-1474.
74. Crosignani Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet. Human Reproduction 18 (2003): 1928-1932.
75. Dunaif A, Scott D, Finegood D, et The insulin- sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. The Journal of Clinical Endocrinology and Metabolism 81 (1996): 3299-3306.
76. Ehrmann DA, Schneider DJ, Sobel BE, et Troglitazone Improves Defects in Insulin Action, Insulin Secretion, Ovarian Steroidogenesis, and Fibrinolysis in Women with Polycystic Ovary Syndrome1. The Journal of Clinical Endocrinology & Metabolism 82 (1997): 2108-2116.
77. Nestler JE, Jakubowicz DJ, Reamer P, et al. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. The New England journal of medicine 340 (1999): 1314-1320.
78. Sepilian V,Nagamani M. Effects of Rosiglitazone in Obese Women with Polycystic Ovary Syndrome and Severe Insulin The Journal of Clinical Endocrinology & Metabolism 90 (2005): 60-65.
79. Raval AD, Hunter T, Stuckey B,et Statins for women with polycystic ovary syndrome not actively trying to conceive. Cochrane Database of Systematic Reviews(2011).
80. Tasali E, Chapotot F, Leproult R, et al. Treatment of Obstructive Sleep Apnea Improves Cardiometabolic Function in Young Obese Women with Polycystic Ovary The Journal of Clinical Endocrinology & Metabolism 96 (2011): 365-374.
81. Helvaci N, Karabulut E, Demir AU,et Polycystic ovary syndrome and the risk of obstructive sleep apnea: a meta-analysis and review of the literature. Endocrine Connections 6 (2017): 437-445.
82. Gangale MF, Miele L, Lanzone A, et Long-term metformin treatment is able to reduce the prevalence of metabolic syndrome and its hepatic involvement in young hyperinsulinaemic overweight patients with polycystic ovarian syndrome. Clinical Endocrinology75 (2011): 520-527.
83. Brown AJ, Tendler DA, McMurray RG,et al. Polycystic Ovary Syndrome and Severe Nonalcoholic Steatohepatitis: Beneficial Effect of Modest Weight Loss and Exercise on Liver Biopsy Findings. Endocrine Practice 11 (2005): 319-324.
84. Greenwood EA, Pasch LA, Cedars MI, et al. Association between depression, symptom experience and quality of life in polycystic ovary syndrome. American journal of obstetrics and gynecology219(2018): 279.e1-279.e7.
85. Zhuang J, Wang X, Xu L, et Antidepressants for polycystic ovary syndrome. Cochrane Database of Systematic Reviews(2013).
86. Escobar-Morreale HF, Botella-Carretero JI, Alvarez- Blasco F, et The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. The Journal of Clinical Endocrinology and Metabolism 90 (2005): 6364-6369.
87. Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus Clomiphene for Infertility in the Polycystic Ovary New England Journal of Medicine 371 (2014): 119-129.
88. Wallach EE, Kelly AC,Jewelewicz Alternate regimens for ovulation induction in polycystic ovarian disease. Fertility and Sterility 54 (1990): 195-202.
89. Tso LO, Costello MF, Albuquerque LE, et al. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. The Cochrane Database of Systematic Reviews (2009): CD006105.
90. Palomba S, Falbo A, Carrillo L, et al. Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin- stimulated in vitro fertilization cycles: a randomized, controlled trial. Fertility and Sterility 96 (2011): 1384- e4.
91. Palomba S, Falbo A,La Sala Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophinsforinvitrofertilisation and intracytoplasmic sperm injection cycles: a systematic review and meta- analysis of randomised controlled trials. BJOG: An International Journal of Obstetrics &Gynaecology 120 (2012): 267-276.