Polycystic Ovarian Syndrome

Etiology

PCOS is a complex multigenic disorder with strong epigenetic factors associated with it.[5] Genome-wide association Studies (GWAS) have identified multiple PCOS-associated genetic loci; many of these genes are involved in various levels of insulin resistance, ovarian steroidogenesis, steroid hormone biosynthesis, PI3K-Akt signaling pathway, adrenal cortisone reductase deficiency [6], and gonadotrophic dysregulation.[6] Twin studies have estimated that about 70% of PCOS pathogenesis is attributable to genetic components.[7] 

The DENND1A (Differentially Expressed in Normal and Neoplastic Development isoform A1) gene was identified as a potential risk marker.[8] Epigenetic factors like obesity affect the hypermethylation of granulosa cells in the ovary, inhibiting gene expression. Some hypotheses also include fetal androgen exposure as an etiology that needs validation.[9] The role of microRNAs in the regulation of GLUT4 implicated in insulin resistance has also been validated.[10][11]

Epidemiology

As evidence is growing, PCOS is being recognized as the most common endocrine pathology in reproductive-aged females worldwide, affecting between 5% and 26% of females. Rotterdam criteria (RC), the most common criteria used in prevalence studies, includes broader criteria than the second most commonly used National Institute of Health 1990 Criteria. The Revised Rotterdam Criteria by Androgen Excess Society (RCAES) is more sensitive in including PCOS phenotype with polycystic ovarian morphology (PCOM) with infertility than RC criteria. The degree of hirsutism was less in women diagnosed using NIH criteria when compared to those diagnosed with RC and RCAES criteria. Those diagnosed with RC criteria had a lower prevalence of insulin resistance (IR) than those diagnosed with NIH and RCAES criteria.[12] Conversely, more than 80% of women who present with hyperandrogenism have PCOS.[13] Based on the NIH 2012 workshop report, PCOS is estimated to affect about 5 million reproductive-aged females in the United States. The cost to the healthcare system for diagnosing and treating PCOS is approximately 4 billion annually, not including the cost of severe comorbidities associated with PCOS.

Multiple conditions have been associated with PCOS, including infertility, metabolic syndrome, obesity, impaired glucose tolerance, type 2 diabetes mellitus, cardiovascular risk, depression, obstructive sleep apnea (OSA), endometrial cancer, and metabolic dysfunction-associated steatotic liver disease (MASLD). Higher prevalence has been associated with first-degree relatives with PCOS, prepubertal obesity, congenital virilizing disorders, above-average or low birth weight for gestational age, premature adrenarche, and the use of valproic acid as an antiepileptic drug. Studies have also suggested a higher prevalence of PCOS among Mexican Americans than among non-Hispanic whites and African Americans.[14][15] Geographical differences in the prevalence of components of diagnostic criteria worldwide and the heterogeneity must be considered.[1] There are changes in phenotypic prevalence of PCOS with women with classic PCOS (type A) decreasing over time to not meeting PCOS criteria in a 5-year long-term follow-up study.[16]

Pathophysiology

The pathophysiology of PCOS is complex and multifactorial with aberrancies in ovarian steroidogenesis, insulin resistance, antimullerian hormone (AMH), and Luteinizing hormone (LH) excess from dysfunction of the hypothalamic-pituitary-ovarian (HPO) axis. These pathways interact in many ways and at many points in the pathogenic chain. However, most recent literature has increasingly recognized it as a metabolic disease.[17] The bidirectional link between hyperinsulinemia and androgen excess is an essential pathogenetic feature.[17] 

Etiologies for this dysregulation involve insulin resistance leading to hyperinsulinemia, which is seen in 70% of females with PCOS. Impaired catecholamine sensitivity to lipolysis has been demonstrated as an early indicator of insulin resistance.[18] Insulin is known to sensitize the ovary to LH by interfering with the process of homologous desensitization to LH in the normal ovulation cycle as well as an intrinsic imbalance among intraovarian regulatory systems, whereas insulin-like growth factors (IGF) interact with FSH in GC cells, influencing follicular maturation and steroidogenesis.

Theca cells in PCOS have overexpression of most steroidogenic enzymes and proteins involved in androgen synthesis, which suggests a prominent abnormality at the level and activity of steroidogenic enzymes, including P450c17, which has been highly identified. Granulosa cells prematurely luteinize primarily as a result of androgen and insulin excess. Additionally, hyperinsulinemia affects IGF1 binding protein and SHBG in the liver and adrenal steroid response to hyperandrogenemia. A positive feedback loop between FSH and IGF1 in GC is essential for follicular dominance and maturation.[19] Impaired IGF1 levels in hyperinsulinemia states can also affect follicular maturation and lead to oligo-ovulation. On the other hand, androgen excess leads to impaired IGF1 levels, potentiating the cycle.[20] Insulin resistance in PCOS is independent of adiposity.[21] Circulating C-reactive protein is elevated in individuals with PCOS, irrespective of obesity, compared to controls, indicating low-grade chronic inflammation.[22]

Two-thirds of PCOS presentations have typical functional ovarian hyperandrogenism, characterized by dysregulation of androgen secretion with an over-response of 17-hydroxyprogesterone (17-OHP) to gonadotropin stimulation. The remaining 20% to 30% of PCOS cases have an atypical FOH response of 17-OHP, but testosterone elevation can be detected after suppressing adrenal androgen production. About 3% of PCOS patients have a related isolated functional adrenal hyperandrogenism. Specific testing for the FOH subpopulation has low clinical utility in the present day.[23] Androgen excess enhances the initial recruitment of primordial follicles into the growth pool. Simultaneously, it initiates premature luteinization and impairs the dominant follicle selection. This results in classical PCOS histopathologic and gross anatomic changes constituting PCOM.

LH excess is common and is necessary for the expression of gonadal steroidogenic enzymes and sex hormone secretion but is less likely to be the primary cause of ovarian androgen excess because of LH-induced desensitization of theca cells. Hyperandrogenemia provokes LH excess, which then acts on theca and luteinized granulosa sustaining cycle. Clinically, the waist-to-height ratio correlates strongly with hyperandrogenism compared to other anthropometric parameters.[24]

Ovarian hormonal dysregulation alters the pulsatile gonadotropin-releasing hormone release, potentially leading to a relative increase in LH versus follicle-stimulating hormone (FSH) biosynthesis and secretion. LH stimulates ovarian androgen production, while the relative decrease of FSH prevents adequate stimulation of aromatase activity within the granulosa cells, decreasing androgen conversion to the potent estrogen estradiol. This becomes a self-perpetuating, noncyclic hormonal pattern. Elevated serum androgens are converted in the periphery to estrogens, mostly estrone.

As conversion occurs primarily in the stromal cells of adipose tissue, estrogen production is augmented in obese PCOS patients. This conversion results in chronic feedback at the hypothalamus and pituitary gland, in contrast to the normal fluctuations in feedback observed in the presence of a growing follicle and rapidly changing estradiol levels. Unopposed estrogen stimulation of the endometrium may lead to endometrial hyperplasia.[25][26][27]

Recently, additional pathways of autoimmune response and chronic inflammation have been identified in animal studies to play a pathogenic role in the follicular development defects of PCOS and fertility outcomes.[28] 

Histopathology

Histological findings from rat models have shown that PCOS rats had multiple follicular cysts with degrading and thin granulosa layers.[29]

History and Physical

Polycystic Ovarian Syndrome Clinical Features

A complete clinical assessment is critical for the diagnosis of PCOS. Diagnosis comprises criteria of which 2 out of 3 consist of history and physical examination elements, including menstrual history, fertility history, obesity, and features of hyperandrogenism. Additionally, PCOS represents a diagnosis of exclusion; therefore, clinical presentation of other conditions should be recognized.

According to the 2023 International Evidence-Based PCOS Guidelines, irregular menstrual cycles are defined as follows:

• Normal in the first year postmenarche as part of the pubertal transition.
• Within 1 to <3 years postmenarche, menstrual cycle intervals <21 or >45 days 
• Within 3 years postmenarche to perimenopause, menstrual cycle intervals <21 or >35 days or <8 cycles per year
• Any cycle 1 year postmenarche with an interval >90 days
• Primary amenorrhea by age 15 or >3 years post thelarche (breast development) [30]

Hair loss patterns can vary widely, often appearing in a vertex, crown, or diffuse pattern. Women with more severe hyperandrogenism may experience bitemporal hair loss and a receding frontal hairline. Additionally, adolescents with severe or treatment-resistant acne, whether to oral or topical antibiotics, may have a 40% chance of developing PCOS. Clinicians should be particularly vigilant for underlying hyperandrogenism in females in their mid-20s to 30s who have persistent or worsening acne.[30]

Hirsutism is characterized by the presence of coarse, dark terminal hairs in a pattern typically associated with males. Signs of virilization, eg, increased muscle mass, reduced breast size, deepening of the voice, and clitoromegaly, are not commonly seen in PCOS. Virilization suggests elevated androgen levels, which warrants further investigation. In such cases, clinicians should be more concerned about the possibility of an androgen-producing tumor in either the ovary or the adrenal gland.[30]

On physical examination, hirsutism should be assessed objectively using the modified Ferrim-Gallwey scoring system.[31] Depending on ethnicity, a modified Ferriman-Gallwey score (mFG) of 4 to 6 should be used to detect hirsutism, acknowledging that self-treatment is common and can limit clinical assessment.[30]

Polycystic Ovarian Syndrome Risk Factors and Phenotypes

Risk factors like a family history of PCOS, fetal androgen exposure, and a family history of metabolic syndrome need to be taken into account. Though 38% to 88% of women with PCOS are either overweight or obese [32], women with PCOS tend to have more abdominal fat accumulation compared to body mass index (BMI)-matched controls.[33] Therefore, a normal BMI should not exclude a diagnosis of PCOS.

The Androgen Excess Society is also cautious that some PCOS patients may have a history of “regular menses” despite being oligo-ovulatory; patients who present with clinical evidence of hyperandrogenism but apparent eumenorrhea should have their ovulatory function evaluated further with progesterone levels.[30][34] The PCOS task force identified 7 phenotypes (A to G) based on hyperandrogenism, hirsutism, oligo-anovulation, and polycystic ovaries.[34] Phenotype A, or classic phenotype, presents evidence of all 4 criteria of hyperandrogenism, hirsutism, oligo/anovulation, and polycystic ovaries, being the most common. Phenotypes ameliorate with age, and an improvement in hyperandrogenism and increased FSH levels are noted.[35]

Evaluation

Polycystic Ovarian Syndrome Diagnostic Criteria

Most society guidelines have accepted that PCOS may be diagnosed if 2 out of the 3 following clinical criteria are present: chronic oligo-anovulation, clinical or biological hyperandrogenism, and PCOM in the absence of any other pathology, which are part of the Rotterdam Criteria. The National Institute of Health criteria also require clinical or biochemical hyperandrogenism and oligo or anovulation; however, the Rotterdam Criteria are the most commonly used.[30]

Newer criteria from the International Evidence-Based Guideline for the Assessment and Management of PCOS 2023 recommend that an adult diagnosis of PCOS requires the presence of 2 out of the following 3 criteria, as well as the exclusion of differential diagnoses with similar clinical features:

• Clinical or biochemical hyperandrogenism
• Ovulatory dysfunction
• Findings of polycystic ovaries on ultrasound or elevated AMH levels [30]

When irregular menstrual cycles and hyperandrogenism are present, neither ultrasound nor AMH testing is necessary for the diagnosis of PCOS in adults. In adolescents, both hyperandrogenism and ovulatory dysfunction must be present for a diagnosis of PCOS. However, ultrasound and AMH testing are not recommended in this population due to their low specificity.[30] Additionally, chronic oligo-ovulation or anovulation may be established based on the history of irregular cycles. Notably, ovulatory dysfunction can still occur with regular cycles; therefore, if diagnostic confirmation of anovulation is needed, serum progesterone levels can be measured.[30]

Excluding disorders that can mimic the clinical features of PCOS is also essential, including thyroid disease, hyperprolactinemia, and atypical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. For this last condition, a measurement of serum 17-hydroxyprogesterone is required, which may need to be followed up with an adrenocorticotropic hormone (ACTH) stimulation test.[36][37][38]

Hyperandrogenism Diagnostic Evaluation

Clinical hyperandrogenism is diagnosed in adult women who present with hirsutism, alopecia, and acne, which can serve as effective clinical indicators of biochemical hyperandrogenism. Healthcare professionals should assess biochemical hyperandrogenism in the diagnosis of PCOS by measuring total and free testosterone. Free testosterone can be estimated using the calculated free androgen index. If levels of testosterone or free testosterone are not elevated, clinicians may consider measuring androstenedione and dehydroepiandrosterone sulfate (DHEAS). However, clinicians should be aware that these markers have lower specificity, and DHEA levels tend to decrease with age.[30]

Laboratories should prioritize using LC-MS/MS assays over direct immunoassays (eg, radiometric and enzyme-linked assays) for assessing total or free testosterone, as direct immunoassays have limited accuracy and exhibit poor sensitivity and precision for diagnosing hyperandrogenism in PCOS. If androgen levels are significantly above laboratory reference ranges, healthcare professionals should consider other causes of hyperandrogenemia, including ovarian and adrenal neoplasms, congenital adrenal hyperplasia, Cushing's syndrome, ovarian hyperthecosis (particularly after menopause), iatrogenic effects, and syndromes associated with severe insulin resistance. However, some androgen-secreting neoplasms may only cause mild to moderate increases in androgen levels. Therefore, taking a clinical history that includes the timing of symptom onset and any rapid progression of symptoms is crucial for evaluating the possibility of an androgen-secreting tumor.[30]

Imaging Findings of Polycystic Ovaries

Ovarian morphology assessment is more accurate when conducted using transvaginal ultrasound. The number of follicles per ovary (FNPO) is the most effective ultrasound marker for detecting polycystic ovary morphology (PCOM) in adults. In addition to FNPO, the number of follicles per cross-section (FNPS) and ovarian volume (OV) are also reliable ultrasound markers for PCOM in adults. An FNPO of ≥20 in at least 1 ovary should be considered the threshold for diagnosing PCOM in adults.[30]

For patients with irregular menstrual cycles and hyperandrogenism, an ovarian ultrasound is not necessary for diagnosing PCOS. Although measuring AMH can be useful for determining a PCOS diagnosis when an accurate ovarian ultrasound is unavailable to assess PCOM morphology, AMH alone cannot be used as a diagnostic tool for PCOS. Furthermore, AMH should not be used for diagnosis in adolescents.[30]

Treatment / Management

Lifestyle Modification 

Lifestyle modifications are the primary and most effective management approach for PCOS treatment. Fertility is likely to return with a modest weight loss of about 5%, which can be achieved through a low-calorie diet that also improves ovarian structure.[39] Lifestyle interventions, eg, exercise alone or a combination of diet, exercise, and behavioral strategies, should be recommended for all women with PCOS to reduce their metabolic dysfunction. Improved metabolic health in these patients can be monitored through observing reductions in central body fat and lipid profile normalization.[30](A1)

Pharmacologic Management

Hormonal contraceptives

The first-line treatment for women with symptomatic PCOS, specifically for issues such as menstrual irregularities, hirsutism, and acne, is a combined hormonal contraceptive. This can be administered as an oral contraceptive (COC), patch, or vaginal ring. The Endocrine Society does not recommend one method over the others.[30](A1)

The progestin component of these contraceptives helps to lower LH levels, which in turn reduces ovarian androgen production and increases levels of sex hormone-binding globulin. Furthermore, some progestins possess direct antiandrogenic properties, inhibiting the activity of 5 alpha-reductase, which prevents the conversion of free testosterone into its more potent form, 5 alpha-dihydrotestosterone. This makes combined hormonal contraceptives particularly effective in managing symptoms of hyperandrogenism and regulating the menstrual cycle.[30](A1)

Identifying any contraindications to hormonal contraceptives in all patients being considered for this therapy is critical. Regarding metabolic effects, higher estrogen levels tend to increase high-density lipoprotein (HDL) cholesterol and decrease low-density lipoprotein (LDL) cholesterol. No significant difference in body weight or fat distribution between women with PCOS and those without has been demonstrated. When prescribing oral contraceptives, an initial dosing of 20 µg of ethinyl estradiol combined with a progestin that has antiandrogenic properties, eg, desogestrel or drospirenone, or one with neutral effects like norethindrone acetate, is recommended. Studies have shown that a combination of COC with low-dose spironolactone is more effective at reducing symptoms and biochemical markers of hyperandrogenism than using metformin alone.[40](A1)

On the other hand, a combination of metformin and low-dose spironolactone has been found to be more effective in alleviating symptoms and improving medication compliance than either medication used separately.[41] Antiandrogens like spironolactone may be considered for treating hirsutism in women with PCOS if there is insufficient response after at least 6 months of using combined oral contraceptives or undergoing cosmetic treatments. Other antiandrogens, eg, cyproterone (at doses over 10 mg per day), finasteride, flutamide, and bicalutamide, carry potential risks of adverse effects and toxicities.(A1)

Metformin 

As the understanding of PCOS shifts towards viewing it as primarily a metabolic disorder being a primarily metabolic disease evolves, metformin and other insulin-sensitizers and their therapeutic utility have taken center stage. Meformin also improves menstrual cycles, abnormal waist-to-hip ratio, and vascular markers in nonobese women with PCOS.[42] (A1)

In adult women with PCOS, metformin may be less effective in improving hirsutism compared to OCPs in the subgroup BMI 25 kg/m² to 30 kg/m². Metformin alone or OCP alone may be less effective in improving hirsutism than metformin combined with OCP. We are uncertain whether there is a difference between the OCP alone and metformin alone compared to metformin combined with the OCP for severe or minor adverse events, except for the OCP versus metformin combined with the OCP, where the OCP may decrease the incidence of severe and minor gastrointestinal adverse events.

Further large, well-designed RCTs that stratify for BMI are needed to evaluate metformin versus OCPs and combinations in women with PCOS, in particular adolescent women. It can be used for menstrual irregularities in patients with a contraindication for hormonal contraceptives.[30] Metformin is commonly used in adolescent monotherapy, and it helps restore normal menses and weight loss and reduce insulin resistance. It can also mildly improve androgen excess symptoms.[43](A1)

Infertility Treatment 

The first-line therapy for infertility in PCOS patients is letrozole. Clomiphene citrate combined with metformin could be used rather than clomiphene citrate alone in women with PCOS with anovulatory infertility and no other infertility factors to improve ovulation and clinical pregnancy rates.[30](A1)

Symptom-based Treatment for Hirsutism, Alopecia, and Acne 

Clinical hyperandrogenism requires long-term treatment and takes several months before effects are evident. Cosmetic interventions should be initiated while medications start working. These can be bleaching and temporary hair removal methods, galvanic or blended electrolysis for localized areas with the experienced operator, or laser photo-epilation for generalized hirsutism. Pharmacological interventions include topical eflornithine for facial hirsutism, which can be an expensive treatment with potentially serious adverse effects if the body absorbs it.

The first-line treatment of hirsutism is low-dose neutral or antiandrogenic oral contraceptives, which effectively lower androgen levels and effects. Additionally, contraceptive properties are beneficial when combined with antiandrogenic drugs because the latter requires reliable contraception as they are highly teratogenic. Mild hirsutism can be treated with OCP alone. Adjuvant antiandrogen administration can be considered for moderate and severe hirsutism and mild hirsutism without adequate hair growth control after 6 months to 1 year of OCP. 

Additional Insulin Sensitizing Treatment in PCOS

GLP-1 agonists 

Treatment with GLP-1 agonists was associated with decreased BMI and testosterone and an improved ovulation rate in obese women with PCOS.[44] Increasing evidence shows that weight loss and insulin sensitivity are higher with GLP-1 agonists than metformin.[45] GLP1 has not yet been approved for the management of PCOS as an indication. A 2-year observational study on maintaining long-term weight loss after a 16-week treatment with semaglutide followed by metformin continuation showed net weight loss and a decrease in circulating testosterone levels during semaglutide use.[46] Further investigation into newer GLP1s for the management of PCOS is indicated. However, using GLP1 for co-morbid FDA-approved indications like OSA, Diabetes Mellitus, Obesity, and heart failure is encouraged, and monitoring of improvement in metabolic and phenotypic parameters of PCOS is encouraged on an individual healthcare practitioner level.(A1)

Myoinositol 

Myoinositol is an over-the-counter food supplement that increases insulin sensitivity. Compared with placebo, insulin sensitivity in women with PCOS was improved without significantly affecting BMI. Data is limited, and its use has been mostly applied as fertility treatment of PCOS or when metformin is not tolerated, given it has fewer gastrointestinal adverse effects.[47](A1)

Bariatric surgery 

General population guidelines should inform bariatric/metabolic surgery in women with PCOS.

Differential Diagnosis

The differential diagnoses for PCOS include the following:

• Use of androgenic steroids
• Hypothyroidism
• Late-onset congenital adrenal hyperplasia
• Idiopathic/familial hirsutism
• Ovarian malignancies

Prognosis

The prevalence of hirsutism and acne decreases with age. Ovarian volume and follicle number also decrease with age, with the age-related decrease in follicle number seemingly greater than ovarian volume.[35] While ovulation rates improve in women with PCOS as they age, successful pregnancies and live births decrease with age.[48] A 41% to 64.8% pregnancy success rate has been identified in females treated with letrozole [49][50], a cumulative live-birth rate of 31% (average 3 attempts) with intrauterine insemination (IUI) [51], and a 29% liver-birth rate for those treated with in-vitro fertilization (IVF).[52]

A population-based retrospective study conducted in a reproductive age cohort from Western Australia demonstrated a high-risk prognosis compared to the general population for more nonobstetric and noninjury-related hospital admissions (median, 5 versus 2; P < .001), a diagnosis of adult-onset diabetes (12.5 versus 3.8%), obesity (16.0 versus 3.7%), hypertensive disorder (3.8 versus 0.7%), ischemic heart disease (0.8 versus 0.2%), cerebrovascular disease (0.6 versus 0.2%), arterial and venous disease (0.5 versus 0.2% and 10.4 versus 5.6%, respectively), asthma (10.6 vs 4.5%), stress/anxiety (14.0 vs 5.9%), depression (9.8 versus 4.3%), licit/illicit drug-related admissions (8.8 versus 4.5%), self-harm (7.2 versus 2.9%), land transport accidents (5.2 versus 3.8%), and mortality (0.7 versus 0.4%) (all P < .001). Women with PCOS had a higher rate of admissions for menorrhagia (14.1 versus 3.6%), treatment of infertility (40.9 versus 4.6%), and miscarriage (11.1 versus 6.1%) and were more likely to require in vitro fertilization (17.2 versus 2.0%)[53]

Despite the higher prevalence of risk factors noted above, a recent 32-year prospective study of PCOS women in the age range (72-91) at the time of assessment showed no evidence of an increase in all-cause mortality or cardiovascular death.[54]

Complications

Infertility 

Endocrine Society Guidelines recommend screening for ovulatory status in all patients. Even a patient with eumenorrheic menstrual cycles may have anovulation, which can be measured by mid-luteal serum progesterone. Excluding other causes of infertility is also recommended. 

Obstetric Complications 

Women with PCOS should be counselled on the adverse impact of excess weight on clinical pregnancy, miscarriage, and live birth rates following infertility treatment [30]

Endometrial Cancer 

Multiple studies have shown an increased risk of endometrial cancer in patients with PCOS. Numerous risk factors are shared between both pathologies. Endocrine Society suggests against routine ultrasound (US) endometrial thickness screening in asymptomatic patients. However, women should be counseled to report unexpected or abnormal uterine bleeding.

Metabolic and Cardiovascular Diseases

Screening for obesity must be conducted for PCOS women and adolescents by calculating BMI and waist circumference. Blood pressure measurement, diabetes, and lipid screening should be performed at diagnosis, and then, follow-up levels should be checked at a frequency based on results. Insulin resistance has been associated highly with PCOS. Around 33% to 66% of patients with PCOS have an abnormal degree of insulin resistance.

Endocrine Society guidelines recommend using an oral glucose tolerance test (OGTT), with fasting and 2-hour glucose after a 75 g OGTT, to screen for IGT and type-2 diabetes mellitus. OGTT is preferred over HbA1c due to its decreased sensitivity in PCOS patients. Rescreening should be conducted every 3 to 4 years due to more frequent risk factors than the general population. Additionally, obese and overweight patients should be screened for symptoms of OSA and referred for sleep studies when this test is positive.

Metabolic Dysfunction-Associated Steatotic Liver Disease  

Women with PCOS have 3 times the increased risk of MASLD, formerly known as nonalcoholic fatty liver disease NAFLD; it has been associated with androgen excess and low sex hormone-binding globulin. Routine measurement of LFT is not recommended unless the patient is overweight or obese, given a low sensitivity and specificity MASLD diagnosis. In these patients, a change in management with newer antidiabetic medications like GLP-1 agonists can decrease the risk of the development of NAFLD.

Depression 

Evidence for the increased rate of depression symptoms was found for PCOS women compared to non-BMI-matched controls. Major depression, recurrent depression, and suicide attempts were also higher in PCOS women. Screening and identifying depression and anxiety disorders should be conducted. Appropriate treatment should be given.