Polycystic ovary syndrome

Polycystic ovary syndrome Poly Cystic Ovarian Syndrome (PCOS) is one of the most common metabolic and reproductive disorders among women of reproductive age. Women suffering from PCOS present with a constellation of symptoms associated with menstrual dysfunction and androgen excess, which significantly impacts their quality of life. They may be at increased risk of multiple morbidities, including obesity, insulin resistance, type II diabetes mellitus, cardiovascular disease (CVD), infertility, cancer, and psychological disorders. Polycystic ovary syndrome (PCOS) is a complex condition characterized by elevated androgen levels, menstrual irregularities, and/or small cysts on one or both ovaries The disorder can be morphological (polycystic ovaries) or predominantly biochemical (hyperandrogenemia). Hyperandrogenism, a clinical hallmark of PCOS, can cause inhibition of follicular development, microcysts in the ovaries, anovulation, and menstrual changes.PCOS is a heterogeneous disorder that affects at least 7% of adult women. According to the National Institutes of Health Office of Disease Prevention, PCOS affects approximately 5 million women of childbearing age in the U.S. Costs to the U.S. health care system for the identification and management of PCOS are approximately $4 billion per year. Research suggests that 5% to 10% of females 18 to 44 years of age are affected by PCOS, making it the most common endocrine abnormality among women of reproductive age in the U.S. Women seeking help from health care professionals to resolve issues of obesity, acne, amenorrhea, excessive hair growth, and infertility often receive a diagnosis of PCOS. Women with PCOS have higher rates of endometrial cancer, cardiovascular disease, dyslipidemia, and type-2 diabetes mellitus.This article explores the pharmacotherapeutic management of PCOS.Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. Depending on diagnostic criteria, 6% to 20% of reproductive aged women are affected. Symptoms of PCOS arise during the early pubertal years. Both normal female pubertal development and PCOS are characterized by irregular menstrual cycles, anovulation, and acne. Owing to the complicated interwoven pathophysiology, discerning the inciting causes is challenging. Most available clinical data communicate findings and outcomes in adult women. Whereas the Rotterdam criteria are accepted for adult women, different diagnostic criteria for PCOS in adolescent girls have been delineated. Diagnostic features for adolescent girls are menstrual irregularity, clinical hyperandrogenism, and/or hyperandrogenemia. Pelvic ultrasound findings are not needed for the diagnosis of PCOS in adolescent girls. Even before definitive diagnosis of PCOS, adolescents with clinical signs of androgen excess and oligomenorrhea/amenorrhea, features of PCOS, can be regarded as being “at risk for PCOS.” Management of both those at risk for PCOS and those with a confirmed PCOS diagnosis includes education, healthy lifestyle interventions, and therapeutic interventions targeting their symptoms. Interventions can include metformin, combined oral contraceptive pills, spironolactone, and local treatments for hirsutism and acne. In addition to ascertaining for associated comorbidities, management should also include regular follow-up visits and planned transition to adult care providers. Comprehensive knowledge regarding the pathogenesis of PCOS will enable earlier identification of girls with high propensity to develop PCOS. Timely implementation of individualized therapeutic interventions will improve overall management of PCOS during adolescence, prevent associated comorbidities, and improve quality of life. , Stein-Leventhal syndrome was the term used for more than 50 years for the heterogeneous clinical features of the disorder now known as polycystic ovary syndrome. Pathophysiology Previous hypothesis Many hypotheses emerged trying to explain the pathophysiology of PCOS. Initially, excess intrauterine androgen had been thought to be a main culprit in the development of the disease. Yet recently, human studies showed neither an association between excessive prenatal androgen exposure and the development of PCOS in youth nor an elevation in androgen levels in the cord blood of females born to mothers with PCOS Another hypothesis, the adipose tissue expandability hypothesis, suggested that infants with intra-uterine growth restriction (IUGR) and spontaneous catch-up growth might develop decreased tissue expandability, meaning that they cannot store lipids appropriately in their fat tissues. Consequently, insulin resistance might ensue contributing to PCOS and hyperandrogenemia However, this does not apply for patients with PCOS who did not have IUGR or had it but without spontaneous catch up Clinical signs of PCOS include elevated luteinizing hormone (LH) and gonadotropin–releasing hormone (GnRH) levels, whereas follicular-stimulating hormone (FSH) levels are muted or unchanged. As a result of the increase in GnRH, stimulation of the ovarian thecal cells, in turn, produces more androgens. Follicular arrest can be corrected by elevating endogenous FSH levels or by providing exogenous FSH.Some studies suggest that PCOS is a primary defect in young girls who are entering puberty and who have a family history of the disorder. Approximately 25% of patients with PCOS have elevated prolactin levels. A Multifaceted disease The best understanding of the pathophysiology of PCOS deals with it as a multifaceted disease involving uncontrolled ovarian steroidogenesis, aberrant insulin signaling, excessive oxidative stress, and genetic/environmental factors. An intrinsic defect in theca cells can partially explain the hyperandrogenemia in patients with PCOS. Indeed, women with PCOS have theca cells that, still secrete high levels of androgens due to an intrinsic activation of steroidogenesis even in the absence of trophic factors This intrinsic dysregulation also affects granulosa cells which produce up to 4 times higher levels of anti-mullerian hormone in women with PCOS in comparison to healthy controls Studies also show an elevated number of follicles, primarily pre-antral and small antral follicles, in females with PCOS A defect in apoptotic processes in some maturing follicles further increases their count in PCOS patients Alternatively, decreased insulin sensitivity attributable to a postreceptor binding defect in the insulin signaling pathways has been identified as an intrinsic component of PCOS, independent of obesity It was also reported an alteration in gene expression of some players in insulin signaling pathways by microarray gene analysis Moreover, PCOS has been associated with increased glycooxidative stress secondary to mitochondrial dysfunction). Oxidative stress can itself induce insulin resistance and hyperandrogenism in patients with PCOS Familial aggregation of PCOS and genomic identification of PCOS-susceptibility loci support the role of genetics in the etiology of this disease. Some studies showed an inherited component of androgen excess in patients with PCOS . Furthermore, a polymorphic marker in fibrillin 3 gene associated with PCOS, D19S884, has been identified in independent sets of families carrying the disease .By the time the diagnosis is established, PCOS presents as a phenotype reflecting a self-perpetuating vicious cycle involving neuroendocrine, metabolic, and ovarian dysfunction. Over the years, numerous hypotheses have been proposed regarding the proximate physiologic origins for PCOS Phenotypes Since PCOS tends to present as a spectrum of diseases, the Rotterdam criteria divided the disease into four phenotypes ➢ Frank or classic polycystic ovary PCOS (chronic anovulation, hyperandrogenism, and polycystic ovaries) ➢ Classic non-polycystic ovary PCOS (chronic anovulation, hyperandrogenism, and normal ovaries) ➢ Non-classic ovulatory PCOS (regular menstrual cycles, hyperandrogenism, and polycystic ovaries) ➢ Non-classic mild or normoandrogenic PCOS (chronic anovulation, normal androgens, and polycystic ovaries) Diagnostic criteria Three sets of diagnostic criteria for polycystic ovary syndrome are used commonly . All require the exclusion of other known disorders.The National Institutes of Health (NIH) conference on PCOS in 1990 led to the first internationally accepted diagnostic criteria. The two criteria (clinical and/or biochemical evidence of hyperandrogenism and menstrual dysfunction) were based on expert opinion solicited through a questionnaire. In 2003 the Rotterdam criteria developed by the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine (ESHRE/ASRM) allowed for the inclusion of polycystic-appearing ovaries on ultrasound. This was defined as 12 or more follicles measuring 2 to 9 mm in at least one ovary, or an ovarian volume greater than 10 mL in the absence of a dominant follicle. The ESHRE/ASRM diagnostic guidelines only required meeting two of three criteria (clinical and/or biochemical hyperandrogenism, oligomenorrhea and/or anovulation, and polycystic ovaries). Most recently, the experts contributing to the Androgen Excess Society (AES) diagnostic guidelines required meeting two criteria (clinical and/or biochemical hyperandrogenism and either ovarian dysfunction or polycystic ovaries). Diagnostic Criteria for the Polycystic Ovary Syndrome Variable National Institutes of Health Rotterdam Androgen Excess and PCOS Society Hyperandrogenism* Hyperandrogenism required Any two of the three features (hyperandrogenism, ovulatory dysfunction, polycystic ovarian morphologic features) required Hyperandrogenism required Oligo-ovulation or anovulation† Ovulatory dysfunction required Any two of the three features (hyperandrogenism, ovulatory dysfunction, polycystic ovarian morphologic features) required Either ovulatory dysfunction or polycystic ovarian morphologic features required Polycystic ovarian morphologic features‡ Not applicable Any two of the three features (hyperandrogenism, ovulatory dysfunction, polycystic ovarian morphologic features) required Either ovulatory dysfunction or polycystic ovarian morphologic features required No. of combinations that meet criteria for the polycystic ovary syndrome Two (hyperandrogenism plus ovulatory dysfunction; hyperandrogenism plus ovulatory dysfunction plus polycystic ovarian morphologic features) Four (hyperandrogenism plus ovulatory dysfunction plus polycystic ovarian morphologic features; hyperandrogenism plus ovulatory dysfunction; hyperandrogenism plus polycystic ovarian morphologic features; ovulatory dysfunction plus polycystic ovarian morphologic features) Three (hyperandrogenism plus ovulatory dysfunction plus polycystic ovarian morphologic features; hyperandrogenism plus ovulatory dysfunction; hyperandrogenism plus polycystic ovarian morphologic features) The Rotterdam criteria are the most widely used for PCOS diagnosis, and like the more liberal AES criteria they allow for different phenotypes of the disorder. Prevalence estimates for PCOS obtained using the Rotterdam and AES criteria (12% to 18%) were up to twice that obtained using the NIH criteria (9%). NIH-defined PCOS is the most common phenotype, and women with this phenotype are most at risk of developing reproductive and metabolic abnormalities, specifically type 2 diabetes. Three tools can be used to diagnose PCOS In 1990, the National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH)hosted a panel of experts who developed the first known criteria for PCOS. Over the next decade, it was discovered that ovarian morphology was a key component in the diagnosis. The European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) sponsored a workshop in Rotterdam. During the workshop, polycystic ovarian morphology on pelvic ultrasound was added to the NICHD/NIH criteria. It was then decided that only two of the three criteria had to be met for a diagnosis of PCOS.  Diagnostic Tools for Polycystic Ovary Syndrome NICHD/NIH Criteria (1990) ESHRE/ASRM Rotterdam Criteria (2003) Androgen Excess Society (AES) Criteria (2006) Hyperandrogenism Oligo-ovulation/anovulation Exclusion of other related disorders Hyperandrogenism Oligo-ovulation/anovulation Polycystic ovaries Hyperandrogenism Oligo-ovulation/anovulation Polycystic ovaries Exclusion of other related disorders In 2006, the Androgen Excess Society (AES) suggested that the NICHD/NIHS criteria could be used with modifications that included the Rotterdam tool. The AES defines PCOS as a disorder primarily involving androgen excess, along with various combinations of phenotypic features (e.g., hyperandrogenemia, hirsutism, oligo-ovulation/anovulation, and/or polycystic ovaries) that may promote a more accurate diagnosisIn 2012, the NIH sponsored an evidence-based methodology workshop on polycystic ovary disease. The expert panel concluded that each criterion has its own strengths and weaknesses; however, the use of multiple criteria was considered confusing, impeding progress in understanding PCOS If PCOS is suspected, a complete medical history, physical examination, blood tests, and a pelvic ultrasound should be performed. A medical history and physical examination provide the physician with information about unexplained weight gain, menstrual cycle abnormalities, male-pattern hair growth, skin changes, and elevated blood pressure (BP). Blood is drawn to assess hormone, glucose, and lipid levels, and a pelvic ultrasound is performed to scan for ovarian cysts During the assessment period, other potential causes associated with reproductive, endocrine, and metabolic dysfunction should be excluded. Physicians should rule out adrenal hyperplasia, Cushing’s syndrome, and hyperprolactinemia before a PCOS diagnosis is confirmed. After PCOS is diagnosed, studies show that more than 50% of patients develop prediabetes or diabetes, and there is an increased risk of myocardial infarction (MI), dyslipidemia, hypertension, anxiety, depression, endometrial cancer, and sleep apnea.Moreover, pregnant women with PCOS should be informed of the increased rates of miscarriage, gestational diabetes, pre-eclampsia, and premature delivery. EVALUATION As PCOS is ultimately a diagnosis of exclusion, other endocrinopathies that have clinical features similar to those of PCOS must be considered. If ovulatory dysfunction exists, ordering tests to rule out causes such as thyroid dysfunction and hyperprolactinemia (e.g., thyroid-stimulating hormone, prolactin assay) is imperative. Considering the possibility of other more serious causes of androgen excess, such as nonclassic congenital adrenal hyperplasia (confirmed with an elevated 17-hydroxyprogesterone level) and androgen-producing tumors (confirmed with total testosterone levels twofold above upper-normal), is also recommended. In the presence of oligomenorrhea or amenorrhea, measurement of serum FSH and estradiol may be warranted to rule out ovarian insufficiency or hypogonadotropic hypogonadism (hypogonadism of hypothalamic or pituitary origin).The most common clinical feature of hyperandrogenism is hirsutism: the growth of excessive hair in a male-type pattern caused by the conversion of vellus hair to terminal hair under androgen effect on the pilosebacous unit. Hirsutism is most commonly assessed using the modified Ferriman-Gallwey scale to quantify the amount of hair growth on various androgen-dependent body areas. However, race and ethnicity play a significant part in hirsutism. Additionally, the Ferriman-Gallwey scoring system can be somewhat impractical in everyday clinical practice, and will be affected by a patient’s recent waxing, shaving, or other depilation. Practically, hirsutism remains largely a self-reported symptom. In the absence of hirsutism, acne may be considered a clinical marker of hyperandrogenism.A strict definition of biochemical hyperandrogenism in PCOS does not exist. A free testosterone index and a free androgen index are thought to be the most sensitive markers of biochemical hypernadrogenemia by the authors of the Rotterdam criteria. However, the assay methods are variable and have significant limitations. Total testosterone is not a sensitive marker of androgen excess, but measurement may be useful if an androgen-secreting neoplasm is suspected.Irregular or absent menstrual cycles are the most common clinical finding of PCOS and are usually identified during history taking Menstrual cycle intervals longer than 35 days are often anovulatory. If menstrual cycles are absent because of ovarian insufficiency this will be indicated by a finding of significantly elevated FSH levels. In PCOS, which is characterized by euestrogenic chronic anovulation, menstrual withdrawal bleeding can typically be induced by a 5-day to10-day course of progesterone or progestin. This provides further support for anovulation being secondary to PCOS and not being the result of ovarian insufficiency or hypogonadotropic hypogonadism  Menses With reactivation of the GnRH pulse generator, increased gonadotropin secretion stimulates ovarian estrogen secretion and follicular development. Estrogen promotes uterine growth and endometrial proliferation; endometrial estrogen exposure eventually culminates in vaginal withdrawal bleeding and menarche. A longitudinal study found that the median age at menarche for American girls was 12.25 years, with lower menarcheal ages in black and Hispanic girls compared with white and Asian girls By age 15 years, 98% of girls will have experienced menarche Contemporary understanding is that it takes 3 to 4 years postmenarche for adult menstrual cyclicity to mature. By the third year after menarche, 10 or more menses occur annually in 90% of adolescent girls Approximately 41% of girls have achieved ovulatory cycles by the fourth gynecologic year Importantly, ovulation may occur despite irregular menses Currently, evidence-based data regarding the first gynecologic year are limited and are largely derived from studies published prior to 2000. A 2018 systemic review of menstrual patterns during the first gynecologic year concluded that menstrual and ovulatory patterns are diverse during this time period. In 22 studies involving >2000 adolescents, frequent menstrual bleeding (<21 days) occurred in 23% and prolonged menstrual bleeding (>30 to 45 days) occurred in at least 33% Definition of Irregular Menses in Adolescent Girls Normal during the first year postmenarche • From 1 to 3 y postmenarche, <21 d or >45 d • From 3 y postmenarche to perimenopause, <21 d or >35 d or fewer than eight cycles per year • From 1 y postmenarche, >90 d for any one cycle • Primary amenorrhea by age 15 y or >3 y after thelarche Polycystic Ovary Morphology Polycystic ovary morphology (PCOM) is defined as enlarged ovaries with increased stroma and more small peripheral cysts. The Androgen Excess–PCOS Society Task Force recommended that PCOM is defined as ≥20 follicles per ovary using a transvaginal probe and high-resolution technology (transducer frequency ≥8 MHz) However, assessment of ovarian morphology is difficult in the adolescent girl because the increased gonadotropin stimulation leads to increased ovarian volume and follicular growth, giving rise to the appearance of multifollicular ovaries in adolescent girls. Additionally, use of transvaginal probes are problematic in adolescent girls. PCOM is an inconsistent finding in adolescent girls and is not associated with anovulation or metabolic abnormalities Hence, ovarian ultrasounds are unnecessary in adolescent girls The ovarian cycle in polycystic ovary syndrome: when it all goes wrong Because no specific sole cause for PCOS has been determined, the most accepted premise is a multifactorial model, where interactions between environmental cues and factors intrinsic to each individual act in consonance toward a common result, which is the development of hyperandrogenemia, a biochemical hallmark of this pathology. This alteration is the main culprit behind most clinical manifestations of PCOS In PCOS, several of the physiological events within the ovarian cycle and folliculogenesis are disrupted. The very beginning of folliculogenesis is compromised due to high levels of Anti-Müllerian Hormone (AMH) AMH is a 560 amino acid peptide of the TGF-β family, which is secreted by granulosa cells (GC) and displays its greatest expression in small antral follicles and exerts powerful inhibition of primordial follicle initiation and follicle sensitivity to follicle-stimulating hormone (FSH). AMH levels progressively decrease as follicles increase in size, and low levels of this hormone appear to be a requirement for transition from the primordial to the primary stage, dominant follicle selection, and progression to ovulation In women with PCOS, elevated levels of AMH appear to play an important role in long term disruption of ovarian physiology with greater AMH concentrations being linked to worse fertility outcomes Feedback disturbances in the hypothalamus-hypophysis-ovary axis (HHOA) are another typical feature of PCOS with increased frequency and amplitude of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) pulsatile secretion. Higher levels of this hormone induce greater androgen synthesis in ovarian theca cells (TC) In turn, hyperandrogenemia induces a decrease in feedback sensitivity to both estradiol and progesterone in gonadotropic hypothalamic cells, reinforcing GnRH and LH hypersecretion This represents the first of many self-perpetuating pathophysiologic cycles in which hyperandrogenemia plays a pivotal role in the development and progression of PCOS, while simultaneously warranting the presence of the clinical manifestations. The constant growth of follicles, along with nonselection of a dominant unit, leads to the hyperstimulation of several of these structures, hence the alternative proposed denomination of “polyfollicular ovary syndromewhich maintains all the characteristic hormonal imbalances. Genetic factors are also considered to play an important role in the development of this syndrome, by setting the stage for abnormally high androgen synthesis in ovarian tissue. The most accepted model proposes a probable Mendelian pattern of inheritance, where key genetic defects would be transmitted to offspring in a dominant autosomal fashion, albeit with widely variable penetrance, dependent on several environmental and epigenetic factors, such as in utero exposure to elevated levels of androgens Notoriously, mutations in the genes of the androgen receptor, sex hormone binding globulin (SHBG), and steroidogenic enzymes may be especially important in predisposing to the development of hyperandrogenemia Polycystic Ovary Syndrome: The Clinical Picture :risk factors In the clinical setting, PCOS presentation is greatly heterogeneous, with a broad clinical manifestation spectrum . Several sets of diagnostic criteria for PCOS are presented in Although the presence of oligomenorrhea indicates ovulatory dysfunction, apparent eumenorrhea does not completely rule out anovulation. Insulin Resistance, Hyperinsulinemia, and Hyperandrogenemia: A Vicious Cycle The role of IR and hyperinsulinemia in the development of PCOS has been thoroughly explored, and it is generally accepted to play an important role in the molecular mechanisms implicated in the androgenic hypersecretion typical of this pathology This has been evidenced by the decrease in fasting insulin levels observed in women with PCOS that undergo insulin-sensitizing pharmacotherapy, which appears to concurrently lower androgenemia and improve ovarian functionalism On the other hand, although this association is usually conceived as a one-way relationship from IR to hyperandrogenemia, pathways through which hyperandrogenemia may perpetuate IR and hyperinsulinemia are currently being proposed. Indeed, in the context of PCOS, IR and hyperandrogenemia may assemble a vicious cycle, continuously stimulating each other in a reciprocal fashion. Moreover, this conjunction of endocrine-metabolic alterations sets the stage for the progressive development of additional comorbidities, both metabolic and cardiovascular, further complicating the management of these patients The main mechanisms are shown in following figure A great deal of attention has been given to the metabolic disturbances that accompany PCOS, as well as to the consequences of these disturbances later in life. Today, insulin resistance is considered the main pathogenic factor in the background of increased metabolic disturbances in women with PCOS which can explain hyperandrogenism, menstrual irregularity, and other metabolic manifestations seen in this disease In 1980, the association between hyperinsulinemia and PCOS was first noted by Burghen et al. who found a significant positive correlation between insulin, androstenedione and testosterone levels among PCOS women. Multiple studies supported a correlation between diabetes and PCOS and showed that insulin-sensitizing drugs and dietary/lifestyle modifications improve hyperandrogenism in patients suffering from PCOS. When the hormone leptin is used as insulin-sensitizing agent, it decreases androgen levels and induces menstruation in affected lean women Other studies showed that 6 months of lifestyle modifications enhanced insulin sensitivity by 70% and significantly reduced anovulation in affected obese women These studies provide support that insulin resistance aggravates hyperandrogenemia (Lungu et This is one of the critical junctures in the treatment of PCOS, which led to the consideration of insulin-mimetic or insulin-sensitizing agents as part of the management of the disease. These agents, as mentioned later in the review, include metformin, myo-inositol supplements, and thiazolidinedione. Finally, according to the Diabetes Prevention Program (DPP) Research Group PCOS patients should be tested for insulin resistanc From Hyperinsulinemia to Hyperandrogenemia: Systematically Disrupting Ovarian Physiology Insulin and Dysregulation of Hypothalamus-Hypophysis Ovary and Adrenal Signaling Insulin may play a part in the development of the typical increased amplitude and frequency of GnRH and LH pulse secretion seen in PCOS. Indeed, elevation of LH and GnRH secretion in response to insulin infusion has been observed in vitro, both in dosedependent and time-dependent fashions This effect may be mediated by insulin in GnRH-secreting cells of the hypothalamus, by potentiating GnRH gene transcription through the MAPK pathway. As a result, increased GnRH synthesis and secretion lead to a subsequent elevation of LH levels. This continuous stimulation would translate into augmented synthesis of ovarian steroid hormones, particularly androgens On the other hand, insulin also reinforces adrenal glands as an alternate androgen source parallel to ovaries, by potentiating hypothalamus-hypophysis-adrenal axis (HHAA) activity at several key sites Insulin and Sex Hormone Binding Globulin Elevated insulin concentrations have been associated with lower levels of SHBG, leading to enhanced bioavailability of androgens Although insulin and the insulin-like growth factor 1 (IGF-1) have been demonstrated unable to directly repress shbg they may be key indirect mediators, as they have been associated with decreased total protein secretion in human hepatic cells Inhibition of SHBG by elevated concentrations of glucose and fructose is also an important component, mediated by downregulation of hepatocyte nuclear factor 4-𝛼 (HNF-4𝛼) activity. Nonetheless, in the context of IR, this is yet another indirect effect, as it relies on high concentrations of these monosaccharides due to dysfunctional insulin signaling and not on insulin activity per se On the other hand, insulin has been shown to repress insulin-like growth factor-1 binding protein (IGFBP1) synthesis in a direct, rapid, and complete way in both the liver and the ovaries, allowing for greater IGF-1 availability, which in turn boosts insulin activity not only in the liver— further contributing to lower SHBG levels—but also in the ovaries, reinforcing PCOS pathophysiology This suppression is mediated by intranuclear thymine-rich insulin response elements (TIRE). Although not all components of the signaling cascade linking the insulin receptor (INSR) with TIRE are currently known, inhibition of GSK-3 through the PI3K pathway appears to be essential in this process Insulin Signaling in Ovarian Tissue and Selective Insulin Resistance Pleiotropy is a distinguishing feature of insulin signaling, being involved in a wide catalogue of physiologic and pathophysiologic roles through distinct, yet interconnected, second-messenger pathways For example, phosphorylation of IRS allows it to act as a docking site for other signaling proteins, such as Grb2, NcK, and PI3K, which are crucial for translocation of GLUT-4. From Hyperandrogenemia Back to Hyperinsulinemia: Completing the Loop Traditionally, the relationship between IR and PCOS is considered to be a unidirectional pathway toward ovarian disturbances. Nonetheless, recent evidence underpins a complex reciprocal interaction between these phenomena. Indeed, in the context of PCOS, hyperandrogenemia per se may affect insulin sensitivity This may be mediated by upregulation of 𝛽3 adrenergic receptors and hormone-sensitive lipase expression in visceral adipose tissue (VAT) through testosterone or DHEAS signaling modifying lipolytic activity and favoring release of FFA into circulation. This increase in FFA availability causes functional and structural changes in hepatocytes and skeletal myocytes, with the accumulation of metabolites from the long-chain FFA reesterification pathway, including Acyl-CoA and diacylglycerol. In turn, these molecules can activate PKC, a serine/threonine kinase which is widely accepted as pivotal for the mechanisms underlying IR, particularly through serine phosphorylation of IRS-1 In PCOS, androgens also appear to modify metabolic architecture and functionality in skeletal muscle, by decreasing the amount of type I muscle fibers, which are highly oxidative and insulin-sensitive, and increasing type II fibers, which are glycolytic and less sensitive, as well as decreasing expression of glycogen synthase Further mechanisms remain poorly characterized, including androgen-driven proinflammatory cytokine secretion from VAT and androgen-induced interference of insulin signaling Obesity, the Adipocyte, and Nutrient Excess Overweight and obesity are common among adolescent girls and adult women with PCOS. In response to nutrient excess, adipocytes can enlarge (hypertrophy) or form new adipocytes (hyperplasia). According to the adipose tissue expandability hypothesis, adipocyte hypertrophy establishes a microenvironment characterized by hypoxia, proinflammatory cytokine secretion, free fatty acid “spillover,” macrophage invasion, and IR . IR decreases suppression of adipocyte lipolysis, resulting in increased serum free fatty acids and triglycerides, ultimately leading to increased hepatic de novo lipogenesis and hyperlipidemia Another consequence is increased fat storage in skeletal muscle, liver, and pancreas because the adipose tissue capacity to store lipid is exceeded. In the liver, ectopic fat storage is labeled hepatic steatosis, which can develop into nonalcoholic fatty liver disease White adipose tissue has several distinct locations, that is, visceral and subcutaneous. Partitioning of fat among different storage sites influences metabolic consequences: increased abdominal fat is associated with greater risk for dysglycemia and cardiovascular disease. Investigation of normal-weight women with PCOS showed increased total abdominal fat mass due to preferential deposition of intra-abdominal fat with an increased population of small subcutaneous abdominal adipocytes In a pilot study involving normal-weight women with PCOS, subcutaneous adipose IR correlated with serum androgen concentrations and the percentage of small subcutaneous abdominal adipocytes. These data support the hypothesis that expansibility of the subcutaneous abdominal adipose depot is limited and unable to expand sufficiently to meet the metabolic needs for most normal-weight women with PCOS Emerging pilot data in adolescent girls with PCOS showed that reduction of visceral fat improved menstrual irregularity In a small cross-sectional study, girls related to women with PCOS showed higher 17-hydroxyprogesterone concentrations, decreased insulin sensitivity, and decreased insulin-induced suppression of nonesterified fatty acid concentrations compared with healthy control girls. These findings suggest onset of adipocyte dysfunction, IR, and possible lipotoxicity among girls aged ∼9 to 15 years In another small study using frequently sampled IV glucose tolerance tests, the authors reported early β-cell dysfunction in first-degree female relatives with overweight/obesity of women with PCOS compared with control girls with overweight/obesity Small sample sizes limit the conclusions that can be drawn from these studies. Nevertheless, the studies hint that β-cell function and insulin sensitivity may differ beginning in childhood and early adolescent years among girls “destined” to develop PCOS Type II diabetes mellitus PCOS confers a substantially increased risk for type 2 diabetes mellitus and gestational diabetes from early ages About 1 in 5 women with PCOS will develop type II diabetes making impaired glucose tolerance a common abnormality in this disease . Cross-sectional and prospective longitudinal studies have consistently shown that women suffering from PCOS have a higher risk of developing type II diabetes mellitus or impaired glucose tolerance compared to control populations matched for age and ethnic background Furthermore, prospective longitudinal studies in young and middle-aged women with PCOS show a higher risk for developing diabetes later in life and is mainly due to an increased prevalence of obesity and insulin resistance among these patients Interestingly, family history of diabetes increases the prevalence of type II diabetes mellitus in PCOS patients. However, the prevalence of diabetes in PCOS patients with no family history of diabetes was still much higher than normal women Even though family history and obesity are major contributors in the development of diabetes in PCOS patients, diabetes can still occur in lean PCOS patients who have no family history, mainly secondary to insulin resistance Cardiovascular disease In 1992, Dahlgren et al. identified a 7 times higher risk of myocardial infarction in patients with PCOS compared to healthy controls However, in 1998, an epidemiological study by Pierpoint et al. showed no difference in the risk between the two groups More recent data showed that patients with PCOS have significantly elevated levels of circulating biomarkers of CVD, including C-reactive protein and lipoprotein A, in comparison to matched controls. Other studies demonstrated a higher burden of indicators of atherosclerosis with early onset cardiovascular dysfunction, i.e., arterial stiffness, endothelial dysfunction, and coronary artery calcification In 2010, the Androgen Excess-PCOS society provided a consensus statement about increased risk of CVD in women with PCOS and developed a guideline to prevent such complication Yet, despite the increased cardiovascular risk markers and the indubitable presence of CVD risk factors in this population, uncertainty remains regarding the increased cardiovascular morbidity and mortality in patients with PCOS Discrepancy between studies might be due to the heterogeneous nature of the populations studied. Therefore, supplementary methodologically rigorous trials are needed to determine the absolute risk of CVD in patients with PCOS throughout age ranges. Infertility Women with PCOS may have reduced fertility due to the associated endocrine and gynecologic abnormalities that impact ovarian quality and function Accounting for up to 90% of ovulatory disorders PCOS-associated persistent periods of anovulation are positively correlated with infertility In 1995, a study reported up to 50 and 25% of women in a PCOS population suffering from primary and secondary infertility respectively More recently in 2015, a study by Hart and Doherty showed that infertility is 10 times more common among women with PCOS in comparison to healthy controlsOn the other hand, some studies suggested that females with PCOS who conceive might suffer from pregnancy-related complications such as gestational diabetes pregnancy induced hypertension , and preeclampsia to a higher extent in comparison to matched controls. Various research data also suggest an increased risk of miscarriage in women with PCOS The influence of PCOS phenotype, whether classic or non-classic, on female fertility remains poorly comprehended. Data describing the effects of PCOS on pregnancy outcomes are also limited and based on small trials. Thorough studies are needed to assess the degree of infertility in PCOS various phenotypes and to understand the reasons for increased negative pregnancy outcomes in this group of women.Concerning the effects on the embryo, women with PCOS are 2.5 times at a higher risk of giving birth to small for gestational age children in comparison to healthy females and offspring show an increased morbidity and mortality compared to control Cancer Females suffering from PCOS present many risk factors associated with the development of endometrial cancer, such as obesity, insulin resistance, type II diabetes mellitus, and anovulation Anovulation triggers an unopposed uterine estrogen exposure. This can subsequently trigger the development of endometrial hyperplasia and ultimately endometrial cancer and As a matter of fact, studies show that women with PCOS have a three-fold increased risk of developing endometrial cancer; which is mostly well differentiated with a good prognosis Regardless, no data support ultrasound screening for endometrial thickness in women with PCOS, which comes in agreement with the American Cancer Society against screening for endometrial cancer in patients with average or increased risk. Yet women should be advised to notify their healthcare provider for any spotting or unexpected bleeding On the other hand, there are limited data to support any association between PCOS and breast and ovarian cancer Hirsutism Hirsutism is the result of elevated circulating free testosterone acting on the pilosebaceous unit to convert vellus hair to terminal hair. Removal of unwanted hairs by electrolysis or mechanical depilation will be a temporary solution if the underlying endocrine disorder is not treated. The androgen effect responsible for hirsutism can potentially be reduced by decreasing androgen production, increasing androgen-binding capacity to reduce circulating levels, or reducing androgen action at the androgen receptor. However, individuals with hirsutism must be counseled to be patient, as response to endocrine therapy takes at least 3 to 6 months in concordance with the hair growth cycle.The oral contraceptive pill (OCP) remains the first-line therapy for hirsutism because of its effect on androgen productionFirst, the estrogen component of the OCP increases sex hormone-binding globulin levels, resulting in greater androgen-binding capacity, and reducing circulating free testosterone levels. Second, the progestin component suppresses pituitary LH production, reducing the stimulation of ovarian theca cell androgen synthesis under LH stimulation. Certain OCP progestins such as drosperinone and cyproterone acetate function as androgen receptor antagonists, and have a theoretical advantage over other progestins. OCP use offers the additional benefit of reducing acne, if present, and provides protection against endometrial cancer and menstrual cycle irregularity.Women with hirsutism who do not respond adequately to OCP treatment may benefit from other anti-androgen therapies such as spironolactone or finasteride.  Neuroendocrine Factors: role of leptin Increased LH pulse frequency, LH pulse amplitude, and increased LH/FSH ratios are described in women with PCOS. The initial features of PCOS emerge during the early pubertal years, concomitant with reactivation of the hypothalamic GnRH pulse generator, increased gonadotropin secretion, and subsequent increased ovarian estrogen production. Loci identified in the genome-wide association studies (GWASs) studies include LHCGR, FSHR, and FSH-β polypeptide (FSHB) genes, emphasizing neuroendocrine contributions to PCOS pathophysiology Hypothalamic neurons in the arcuate nucleus secrete kisspeptin, neurokinin B, and dynorphin. These neurons, labeled as the KNDy neurons, are the leading contenders for the hypothalamic GnRH pulse generator because of the colocalization of these three peptides and their roles in episodic GnRH secretion Rather than initiating puberty, the GnRH pulse generator and GnRH neurons represent downstream nodes modulated by other hormones and neurosecretory factors In other words, activation of excitatory inputs and inactivation of inhibitory inputs moderated by multiple influences regulate the output of the GnRH pulse generator to govern the timing of pubertyThis process culminates in increased GnRH and gonadotropin secretion.The hypothalamic GnRH neurons secrete GnRH in discrete pulses that travel through the median eminence to the pituitary gonadotrophs, resulting in pulsatile LH and FSH secretion LH and FSH pulse frequencies are modulated by GnRH pulse frequency. Increased GnRH pulse frequency increases LH pulse frequency and decreases FSH pulse frequencyThe GnRH neurons integrate diverse influences, decode metabolic signals, and serve as the output “managers” of the HPO axis Increased LH pulse amplitude and pulse frequency observed in PCOS are likely driven by increased pulsatile GnRH secretion. Manipulation of the hypothalamic kisspeptin–neurokinin B–GnRH pathway with an NK3 receptor antagonist, AZD4901, reduced serum LH pulse frequency and, subsequently, serum LH and testosterone concentrations. These data suggest the possibility of targeting neuroendocrine pathophysiology to treat HPO axis dysfunction in PCOS GnRH neurons express estrogen receptor-β, but they do not express AR, progesterone receptor, or estrogen receptor-α. Hence, steroid-mediated negative feedback is indirect and is mediated through the hypothalamic neuronal network upstream of the GnRH neuron. This negative feedback mechanism is impaired in some women with PCOS who appear to require higher progesterone and estradiol concentrations. This effect can be abrogated with androgen antagonist treatment Psychological disorder Psychological stress and PCOS have been shown to be intimately related. A vast number of studies showed that women with PCOS are more prone to suffer from psychological disorders such depression , anxiety recreational drug-related incidents disordered eating, and psychosexual dysfunction in comparison to healthy female controls. In addition, females with PCOS have a lower self-esteem and body satisfaction and subsequently tend to have more psychiatric hospital admissions than controls As a result, they display a low quality of life (Jones and are prone to a high degree of emotional distress It is worth noting that obesity acne, hirsutism all associated with PCOS, are major contributors to the psychological stress that the patients experience due to the challenging of the female identity and her body image What cause it? Doctors don’t know exactly what causes PCOS. They believe that high levels of male hormones prevent the ovaries from producing hormones and making eggs normally.Genes, insulin resistance, and inflammation have all been linked to excess androgen production. Genes Twin studies suggest that the hereditability is ∼70% The few identified genetic loci explain only a modest proportion of estimated hereditability. GWASs involving women of Han Chinese and European origins have identified at least 16 susceptibility loci for PCOSSeveral genetic variants are similar in both Han Chinese and European populations, implying that PCOS is an ancient disease Several novel loci have recently been identified .A meta-analysis showed that identified loci are linked to genes plausibly associated with the metabolic and reproductive characteristics of PCOS Linkage disequilibrium score regression analysis demonstrated genetic correlations with metabolic traits, that is, fasting insulin, lipid levels, and PCOS. With the exception of the GATA4/NEIL2 locus, the genetic architecture did not differ whether National Institutes of Health or Rotterdam criteria were used to diagnose PCOS .Genes involved in HPO axis function, that is, LHCGR, FSHR, and FSHB, were identified in these GWASs implicating gonadotropins in the pathophysiology of PCOSUsing family-based quantitative trait meta-analysis, rare DENND1A variants were associated with metabolic and reproductive traits in PCOS families; these data are consistent with the hypothesis that complex disorders such as PCOS are associated with genetic variations in noncoding regions .Epigenetic modifications such as changes in methylation and miRNAs offer another level of regulation affecting the PCOS phenotype. Epigenetic variants have been reported for adipose tissue and muscle studies show that PCOS runs in families It’s likely that many genes — not just one — contribute to the condition Insulin resistance Up to 70 percent of women with PCOS have insulin resistance, meaning that their cells can’t use insulin properly Insulin is a hormone the pancreas produces to help the body use sugar from foods for energy.When cells can’t use insulin properly, the body’s demand for insulin increases. The pancreas makes more insulin to compensate. Extra insulin triggers the ovaries to produce more male hormones.Obesity is a major cause of insulin resistance. Both obesity and insulin resistance can increase your risk for type 2 diabetes  Inflammation Women with PCOS often have increased levels of inflammation in their body. Being overweight can also contribute to inflammation. Studies have linked excess inflammation to higher androgen level The most common PCOS symptoms are: Irregular periods. A lack of ovulation prevents the uterine lining from shedding every month. Some women with PCOS get fewer than eight periods a year Heavy bleeding. The uterine lining builds up for a longer period of time, so the periods you do get can be heavier than normal. Hair growth. More than 70 percent of women with this condition grow hair on their face and body — including on their back, belly, and chest  Excess hair growth is called hirsutism. Acne. Male hormones can make the skin oilier than usual and cause breakouts on areas like the face, chest, and upper back. Weight gain. Up to 80 percent of women with PCOS are overweight or obese Male-pattern baldness. Hair on the scalp gets thinner and fall out. Darkening of the skin. Dark patches of skin can form in body creases like those on the neck, in the groin, and under the breasts.  Headaches. Hormone changes can trigger headaches in some way Treatment The management of PCOS targets the symptomatology for which patients usually present, anovulation, infertility, hirsutism, or acne being the most common complaints. Treatment usually requires the corroboration of an interdisciplinary team that can include a family practitioner, a gynecologist, and endocrinologist, a dermatologist, a pediatrician, a psychiatrist, and a psychologist. Non pharmacological Approaches Because the primary cause of PCOS is unknown, treatment is directed at the symptoms. Few treatment approaches improve all aspects of the syndrome, and the patient’s desire for fertility may prevent her from seeking treatment despite the presence of symptoms.Treatment goals should include correcting anovulation, inhibiting the action of androgens on target tissues, and reducing insulin resistance.Weight reduction for obese patients with PCOS is beneficial in many ways. Weight loss helps to decrease androgen, luteinizing hormone (LH), and insulin levels. It also helps to regulate ovulation, thereby improving the potential for pregnancy.Laparoscopic ovarian drilling is an outpatient surgical intervention in which multiple perforations are created in the ovarian surface and stroma.It is thought that this intervention destroys androgen-producing tissue, which should lead to decreased androgen levels. It has been found to be as effective as medical interventions without increasing the risk of multiple pregnancies. Lifestyle changes Guidelines recommend exercise therapy and calorie-restricted diet as a crucial part of the management of obesity in women with PCOS. In fact, lifestyle modifications are considered as a cost-effective first line treatment and as a necessary adjunct to medication Excessive weight, as previously mentioned, is associated with adverse metabolic and reproductive health outcomes in women with PCOS. For instance, female fertility significantly decreases with a BMI >30–32 kg/m2 Multiple small uncontrolled trials have shown that a body weight decrease of as little as 5% regulates the menstrual cycle, improves fertility, reduces insulin and testosterone levels, decreases the degree of acne and hirsutism, and benefits psychological wellbeing However, so far, neither a specific diet nor exercise schedule has been shown to be superior to another in the management of PCOS. In addition, it is difficult to ascertain the effectiveness of such interventions based on the limited data which sometimes address specific subgroups of women with PCOS. Further studies are needed to compare the efficacy of the different lifestyle management techniques (diet alone or exercise alone in comparison to a combination of both) with or without medical therapy for all associated clinical outcomes. Medical treatment If lifestyle changes are not enough to resolve symptomatology, medical treatment is added for better management of the patient's complaints. Oral contraceptive pills OCP are the most commonly used medications for the long-term treatment of women with PCOS and have been recommended by the Task Force and the Endocrine Society the Australian Alliance and the PCOS Consensus Group as first-line treatment for hyperandrogenism and menstrual cycle irregularities in women with PCOS.By suppressing the hypothalamo-pituitary-ovarian axis, OCP decrease LH secretions, increase sex hormone binding globulins, and decrease free testosterone levels .This addresses hyperandrogenism-mediated symptoms improving acne and hirsutism corrects menstrual cycle abnormalities, and provides a mean for effective contraception A minimum of 6 months of OCP regimen is usually required to obtain satisfactory results against acne and hirsutismEven though guidelines do not specify the use of one OCP over another the best choice for symptomatic treatment is considered to be low-dose oral contraceptives that contain anti-androgenic or neutral progestins A number of clinical trials associated the use of OCP in patients with PCOS with increased risk of insulin resistance Concerns have been also raised about the negative effects of OCP on the cardiovascular profile of females with PCOS Nevertheless, data from randomized control trials and observational studies demonstrated that OCP are indeed effective and safe for the treatment of patients with PCOS with their benefits outweighing their Metformin Metformin (Glucophage), an oral anti-diabetic biguanide drug, acts by impeding hepatic glucose production and increasing the peripheral insulin sensitivity . The earliest studies on PCOS patients using metformin were performed in 1994 by Velazquez et al the results revealed a 35% reduction in the insulin area and a 31% decrease in insulin area to glucose ratio Some data revealed that metformin does not improve insulin resistance itself, rather it improves glucose effectiveness, i.e., the ability of glucose per se to repress endogenous glucose synthesis and stimulate glucose uptake Metformin treatment of obese adolescents with PCOS and impaired glucose tolerance proved beneficial in improving glucose tolerance and insulin sensitivity, in lowering insulinemia, and in reducing elevated androgen levels In contrast, one study performed by Tang et al. showed no significant change in insulin sensitivity in PCOS patients receiving metformin. This could be explained by the high level of obesity (BMI>30 Kg/m2) and the limited weight loss the patients in the study could attain Similarly, Ehrmann et al. showed that metformin did not improve insulin resistance in PCOS women Acbay et al. stated that metformin has no tangible effect on insulin resistance in PCOS patients Thiazolidinediones Thiazolidinediones (TZD) represent a class of insulin sensitizer drugs used in the treatment of type II diabetes mellitus. They activate the gamma isoform of the peroxisome proliferator-activated receptor, which is an adipocyte transcription factor The use of pioglitazone one member of this class, was studied in patients with PCOS and data showed that its administration results in a decline in fasting serum insulin levels and insulin resistance (Brettenthaler et However, following the association of pioglitazone with increased risk of bladder cancer it has been recommended against its use or the use of other TZDs (specifically troglitazone and rosiglitazone) in the treatment of PCOS due to major safety concerns Inositol Recently, new drugs are being marketed as a novel treatment of PCOS and are gaining more recognition due to their lack of side effects. These are myo-inositol (MYO) and D-chiro-inositol (DCI), 2 stereoisomers of inositol, an insulin-sensitizing molecule.Growing evidence suggests that insulin resistance might be induced by an alteration of the metabolism of inositol phosphoglycans (IPG) second messengers and mediators or by a defect in their tissue availability Many trials demonstrated that MYO administration improves insulin resistance in PCOS patients One study reported that the decline in insulin resistance is positively correlated with increasing fasting insulin plasma levels, which supports the role of inositol as a modulator of insulin-mediated metabolic pathway More recent studies assessed the effect of MYO in combination with other new drugs. For instance, when combined with monacolin K (natural statin) and lipoic acid, inositol showed a dose-dependent improvement in dyslipidemia and hyperandrogenism-associated symptoms When combined with folic acid, MYO decreased hyperstimulation syndrome to a higher extent than folic acid alone in PCOS females undergoing oocyte retrieval MYO also improved reproductive outcomes in those undergoing IVF when it was combined with α-lipoic acid .More importantly, the combination of MYO with DCI in a physiological plasma ratio of 40–1 led to a decrease in the risk of developing metabolic syndrome in obese women with pcos Spironolactone One study showed that spironolactone, a steroid chemically related to the mineralocorticoid aldosterone, was able to improve insulin sensitivity; it also suggested its use for hyperandrogenism-associated symptoms such as acne and hirsutism .Accordingly, guidelines do not provide any specific recommendations for the use of spironolactone in the management of PCOS; further methodological studies are required to assess any benefit, if existent, for spironolactone in the treatment of this disease. Treatment in adolescents So far, no placebo-controlled randomized controlled trials for the treatment of PCOS in adolescents have been conducted. As such, treatment recommendations mainly represent an extrapolation of adult gathered data and are still highly controversial. Recommendations suggest individualizing treatment of adolescents with PCOS for benefits to outweigh risks. However, these recommendations are not to be applied to girls with precocious puberty due to unestablished risk-benefit ratio in this population .The mainstay of therapy for adolescents with PCOS is OCPs, provided as both treatment of hyperandrogenism and as an effective contraception method .OCPs normalize menses and decrease acne and hirsutism Lifestyle therapy and weight loss is also considered as part of the first line treatment, especially in obese adolescents, as it also improves acne and hirsutism. Nevertheless, uncertainty remains regarding the best OCPs and their appropriate duration of use in adolescents .Alternatively, metformin has been shown to improve hyperandrogenemia, menstrual irregularity, and insulin resistance in obese and non-obese adolescents with PCOS Screening recomendation Screening for type II DM Women with PCOS should be routinely screened for type II DM. Studies have shown that measurement of fasting blood glucose levels alone under-diagnoses type II DM in patients with PCOS, missing up to 80% of pre-diabetic and 50% of diabetic cases As such, guidelines currently recommend screening women with PCOS using an oral glucose tolerance test The screening could be done every 3–5 years or every second year in patients with no risk factors for type II DM and annually in patients with risk factors . Examples of relevant risk factors include age, gender, ethnicity, parental history of diabetes, history of high blood glucose levels, use of antihypertensive medications, smoking, physical inactivity, and waist circumference Screening for CVD Women with PCOS should be routinely screened for CVD risk factors. Guidelines recommend cigarette smoking assessment, body weight and BMI measurements to check for obesity, blood pressure monitoring to evaluate for hypertension, and a complete lipid profile panel (total cholesterol, low density lipoprotein cholesterol LDL-C, high density lipoprotein cholesterol HDL-C, and triglycerides levels) to screen for dyslipidemia . It is important to note that the Australian guideline dwells in depth in its CVD screening recommendations, indorsing blood pressure measurement annually if BMI ≤ 25 kg/m2 or at each visit if BMI ≥ 25 kg/m2 and lipid profile assessment every 2 years if initially normal or every year if initially abnormal. Screening for psychological wellbeing Guidelines recommend screening women with PCOS should be screened for not only depression and anxiety but also for negative body image, eating disorders, and psychosexual dysfunction If screening is positive, the health physician should further assess the problem and refer the patient to a specialist if needed. MANAGEMENT Treatment decisions are informed by patient priorities, the likely effectiveness and potential risks of available therapies, and whether the woman wishes to become pregnant .Typical therapeutic targets include hirsutism, irregular menses (and the risk of endometrial hyperplasia), and infertility. Although subfertility is a characteristic of the polycystic ovary syndrome, pregnancy without medical assistance is common and contraception should be used as indicated. One study suggested that among patients with the polycystic ovary syndrome who had previously attempted to conceive, two thirds had received treatment for infertility at some point in the past and two thirds had had at least one pregnancy without medical assistance Available treatments do not reverse the underlying disorder, although sustained weight loss may be an exception in some obese women with the polycystic ovary syndrome. Weight loss of as little as 5 to 10% can reduce cardiometabolic risk factors and androgen levels and improve menstrual function and possibly fertilityMechanical hair removal (e.g., shaving and plucking) may be adequate to address hirsutism, but when pharmacologic therapy is needed, combined hormonal (estrogen–progestin) oral contraceptives are considered to be first-line agents. Combined oral contraceptives suppress gonadotropin secretion and ovarian androgen production, and the estrogen component increases hepatic production of sex hormone–binding globulin, decreasing androgen bioavailability. Combined oral contraceptives reduce new terminal hair growth, although many patients still require concomitant mechanical hair removal for well-established hirsutism. Since changes in the quality of terminal hair begin at the hair root, altered hair shafts may not become visible for up to 6 months. Monophasic combined oral contraceptives containing progestins with low androgenic potential (e.g., ethinyl estradiol [35 μg] plus norgestimate [0.25 mg]) are commonly used in women with the polycystic ovary syndrome, although no particular combined oral contraceptive has proved to be superior for clinical hyperandrogenism. Other benefits of combined oral contraceptives include amelioration of acne, regular withdrawal bleeding that contributes to prevention of endometrial hyperplasia, and contraception. Management of Metformin reduces hyperinsulinemia and lowers serum testosterone levels by approximately 20 to 25% in women with the polycystic ovary syndrome. However, its effects on hirsutism are modest at best, and it is not recommended for this indication Metformin may improve ovulatory function. Meta-analyses of randomized, placebo-controlled trials involving women with the polycystic ovary syndrome have shown increased pregnancy rates but not increased live birth rates among women who received metformin; this agent is not recommended as a first-line agent for anovulatory infertility. Metformin is recommended for women with the polycystic ovary syndrome and impaired glucose tolerance or type 2 diabetes that does not respond adequately to lifestyle modification. Given the favorable metabolic effects of metformin, it is plausible that it could provide a long-term cardiovascular benefit to women with the polycystic ovary syndrome, but confirmatory data are lacking. Prevention of endometrial hyperplasia (endometrial protection) may be achieved with the use of combined hormonal contraceptives, intermittent or continuous progestin therapy, or a levonorgestrel-releasing intrauterine device (IUD) When episodic progestins are used, induction of withdrawal bleeding every 1 to 3 months is recommended.  Management of Clomiphene is generally considered to be the first-line agent for induction of ovulation in women with the polycystic ovary syndrome. A randomized trial of ovulation induction involving women with the polycystic ovary syndrome and infertility showed a higher live birth rate among women who received clomiphene than among women who received metformin alone (22.5% vs. 7.2%). However, a subsequent randomized trial showed a higher live birth rate among women who received the aromatase inhibitor letrozole than among women who received clomiphene (27.5% vs. 19.1%) this suggests a potential role for letrozole as initial therapy. In some cases, ovarian stimulation with exogenous gonadotropins or advanced reproductive techniques (e.g., in vitro fertilization) may be required.  Management of Hirsutism Acknowledgment of the significance of the hirsutism, irrespective of the severity, for a particular adolescent is important when offering treatment options as well as understanding expectations of the treatment Long-term commitment is required for any topical and/or medical interventions. More severe hirsutism may require a combination of strategies. Current available therapies have been mostly evaluated in women and include physical hair removal methods, topical medications, light-based therapies, COCPs, and antiandrogens Physical hair removal methods include waxing, shaving, chemical epilation, plucking, bleaching, and electrolysis. All but electrolysis are temporary hair removal methods, easily available and commonly used by adolescents even before they are evaluated for PCOS. 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