Polycystic ovary syndrome.pdf

Polycystic ovary syndrome Straight to the point of care Last updated: Feb 09, 2024  Table of Contents Overview 3 Summary 3 Definition...

Polycystic ovary syndrome Straight to the point of care Last updated: Feb 09, 2024  Table of Contents Overview 3 Summary 3 Definition 3 Theory 4 Epidemiology 4 Aetiology 4 Pathophysiology 5 Classification 6 Case history 6 Diagnosis 8 Approach 8 History and exam 13 Risk factors 15 Investigations 17 Differentials 22 Criteria 25 Management 26 Approach 26 Treatment algorithm overview 33 Treatment algorithm 36 Emerging 61 Primary prevention 62 Secondary prevention 63 Patient discussions 63 Follow up 64 Monitoring 64 Complications 65 Prognosis 67 Guidelines 69 Diagnostic guidelines 69 Treatment guidelines 70 Online resources 72 References 73 Images 98 Disclaimer 101 Polycystic ovary syndrome Overview Summary Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. A leading cause of infertility and pregnancy complications. OVERVIEW Associated with insulin resistance, metabolic syndrome, metabolic dysfunction-associated steatotic liver disease (formerly non-alcoholic fatty liver disease), and increased risk of developing type 2 diabetes. Main treatment goals are to reduce hyper-androgenism or to induce fertility. Letrozole and clomifene are considered first-line pharmacological treatments for infertility in PCOS. Increasing evidence suggests that letrozole may be superior to clomifene. Definition PCOS includes symptoms of hyper-androgenism, presence of hyper-androgenaemia, oligo-/anovulation, and polycystic ovarian morphology on ultrasound. This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 3 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Theory Epidemiology PCOS affects about 6% of women of reproductive age in the US and Europe using the 1990 National Institutes of Health criteria, 10% to 15% of women using the Androgen Excess and PCOS Society criteria, THEORY and 10% to 20% of women using the 2003 Rotterdam criteria. Similar rates are reported in China (10%) and Mexico (6%), suggesting the prevalence does not vary across ethnicities or different regions of the world. There do seem to be differences in the phenotype of PCOS within and between countries. For example, studies report greater impairments in glucoregulatory status in Hispanic compared with white women in the US, and lower rates of ovulatory PCOS in the US compared with Europe. The reported frequency of hirsutism is lower in East Asia and higher among indigenous Australians. There have been no prospective studies that document incidence rates for PCOS. PCOS accounts for 80% to 90% of cases of hyper-androgenism in women. In one large series of women presenting with androgen excess or ovulatory dysfunction, approximately 80% had PCOS, 3% had the hyper- androgenism-insulin resistance-acanthosis nigricans syndrome, 1.5% had 21-hydroxylase-deficient non- classic adrenal hyperplasia, 0.6% had 21-hydroxylase-deficient classic adrenal hyperplasia, and 0.2% had androgen-secreting tumours. Men in families with PCOS may have manifestations including excessive hairiness, premature male-pattern baldness, elevated levels of dehydroepiandrosterone sulfate, abnormal hormonal responses to dynamic testing, and aberrations in insulin sensitivity and secretion. Aetiology The aetiology of polycystic ovary syndrome (PCOS) is unknown. It is a syndrome wherein multiple systems are affected and the site of the primary defect is unclear. Various lines of evidence have supported primary defects in the hypothalamic-pituitary axis, postulating increased amplitude and frequency of pulses of luteinising hormone (LH), or defects involving the ovaries through an intrinsic problem leading to androgen over-production. Some theories postulate defects in insulin sensitivity with insulin resistance leading to compensatory hyper-insulinaemia. PCOS appears to be inherited as a common complex disorder. Multiple genes, each with mild or moderate effects on overall disease risk, are likely to be involved. One twin study calculated the heritability of PCOS at 70%, suggesting that most PCOS risk depends on genetic factors. The actual PCOS susceptibility genes have yet to be definitively identified. A large genome-wide association study conducted in Chinese individuals robustly identified genetic variants in or near 3 genes (DENND1A, THADA, LHCGR) as risk factors for PCOS. Variation in DENND1A was subsequently associated with PCOS in several European-origin cohorts. A subsequent genome-wide association study in Chinese individuals increased the number of susceptibility loci to 11. Three genome-wide association studies in predominantly European-origin cohorts increased the total number of PCOS susceptibility variants to 25. Most loci discovered in one ethnic group appear to affect PCOS risk in other ethnic groups, suggesting an ancient origin of PCOS. Susceptibility loci include genes for the LH receptor, the follicle- stimulating hormone receptor, and the follicle-stimulating hormone beta sub-unit, suggesting a key role for disordered gonadotrophin function in PCOS. Epigenetic changes (DNA alterations independent of the primary nucleotide sequence; e.g., DNA methylation) may also play a role in PCOS susceptibility, as evidenced by differential X-chromosome inactivation in PCOS. 4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Theory Pathophysiology The pathophysiology of PCOS is not well understood, mainly due to lack of knowledge of the location THEORY of the primary defect. There are several candidates: ovary, adrenal, hypothalamus, pituitary, or insulin- sensitive tissues. It is possible that there are subsets of women with PCOS wherein each of these proposed mechanisms serves as the primary defect. Simplified diagram of the main pathogenic factors in PCOS. ACTH, adrenocorticotrophic hormone; FSH, follicle-stimulating hormone; GnRH, gonadotrophin-releasing hormone; LH, luteinising hormone From the collection of Dr M.O. Goodarzi; used with permission Investigations have elucidated some of the interactions between these systems. Insulin resistance leads to compensatory insulin hypersecretion by the pancreas in order to maintain normoglycaemia. The resulting hyperinsulinaemia promotes ovarian androgen output and may also promote adrenal androgen output. High insulin levels also suppress hepatic production of sex hormone-binding globulin, which exacerbates hyper- androgenaemia by increasing the proportion of free circulating androgens. Another factor that promotes ovarian androgen output is the fact that women with PCOS are exposed long term to high levels of LH. This LH excess seems to be a result of an increased frequency of gonadotrophin-releasing hormone pulses This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 5 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Theory from the hypothalamus. The abnormal hormonal milieu may also contribute to incomplete follicular development that results in polycystic ovarian morphology. Classification THEORY Proposed classification There is no formal classification system for PCOS. The following has been proposed: Mild PCOS (accounts for 16% of affected women): characterised by irregular periods, polycystic ovaries on ultrasound, mildly elevated androgen concentrations, normal insulin concentrations, unknown long-term risks Ovulatory PCOS (accounts for 16% of affected women): characterised by normal periods, polycystic ovaries on ultrasound, elevated androgen concentrations, increased insulin concentrations, unknown long-term risks Hyper-androgenism and chronic anovulation (accounts for 7% of affected women): characterised by irregular periods, normal ovaries on ultrasound, elevated androgen concentrations, increased insulin concentrations, potential long-term risks Severe PCOS (accounts for 61% of affected women): characterised by irregular periods, polycystic ovaries on ultrasound, elevated androgen concentrations, increased insulin concentrations, potential long-term risks. Case history Case history #1 An 18-year-old woman presents with a chief complaint of hirsutism. She needs to wax her upper lip and chin twice a week. This has been a problem for 4 years. She also has excess hairs on her upper back and lower abdomen. Her periods are irregular, occurring every 2-3 months. Embarrassment about the facial hirsutism has affected her social life, and she is finding she feels depressed much of the time. Case history #2 A 32-year-old woman presents with a chief complaint of difficulty becoming pregnant. She was prescribed oral contraceptives at the age of 17 years because of irregular periods (4-6 periods per year). She continued with oral contraception until 30 years of age, at which point she and her husband decided they wanted to have a baby. Since ceasing oral contraception, she has gained weight and has only 3 to 5 periods per year. She has actively been trying to conceive, with no results. Other presentations The most common presentations are hirsutism and infertility. Women typically present with oligo- or anovulation, manifesting as infrequent, irregular menstrual periods. Polycystic ovary syndrome (PCOS) may also more rarely present with irregular and heavy menstrual bleeding. Some women present with regular menses and hirsutism, and on further investigation are found to have anovulatory cycles. There are no pathognomic features that suggest PCOS. It is largely a diagnosis of exclusion. 6 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Theory THEORY This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 7 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Diagnosis Approach There are no pathognomonic features that suggest polycystic ovary syndrome (PCOS), and it is largely a diagnosis of exclusion. History Common features include hirsutism (affecting 60%), acne (20%), and scalp hair loss (5%); irregular and infrequent periods (often 3 years after breast development). Oligo- or anovulation may manifest irregular as menstrual bleeding, defined as >90 days for any one cycle 1 year post menarche; 45 days for those 1 to 88 cm). Women may have elevated blood pressure as a part of the hypertension sometimes associated with this syndrome. Acanthosis nigricans, usually subtle, may be seen more in obese women with PCOS. 8 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Diagnosis DIAGNOSIS Acanthosis nigricans involving the axilla of an obese white woman From the collection of Melvin Chiu, MD, UCLA; used with permission Sweating or oily skin may occur. Investigations Hirsutism present The diagnosis of PCOS can be made when infrequent/reduced menstrual bleeding also exists. If infrequent/reduced menstrual bleeding is not present in a hirsute woman, evaluate for presence or absence of ovulation (by luteal-phase progesterone measurement or basal body temperature monitoring). Anovulatory cycling may occur, particularly in hirsute women. If such measures are consistent with anovulation, PCOS may be diagnosed in hirsute women. If the hirsute woman has ovulatory cycles, the next step is to perform a transvaginal ultrasound to examine the ovaries. If polycystic ovarian morphology is documented, then PCOS can be diagnosed. In adults, pelvic ultrasound may be replaced by serum anti-Mullerian hormone (AMH) levels. This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 9 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Diagnosis Polycystic ovaries are present in 75% of women with PCOS, but are also seen in up to 25% of normal women and women with other endocrinopathies such as congenital adrenal hyperplasia, hyperprolactinemia, or hypothalamic amenorrhoea. Ultrasound should be done in the early follicular phase (day 3-5) after a spontaneous or progestin-withdrawal-induced menstruation, or randomly in women with infrequent/reduced menstrual bleeding. If evidence of a dominant follicle (>10 mm) or a corpus luteum is seen, the ultrasound should be repeated at the next cycle. Polycystic ovarian morphology is a risk factor for ovarian hyperstimulation syndrome in women undergoing ovulation induction (with clomifene or gonadotrophins). Therefore, an ultrasound before ovulation induction may be useful. If endometrial thickening is found, an endometrial biopsy is indicated to determine whether endometrial hyperplasia or cancer is present. Routine ultrasound screening for endometrial thickness is not recommended. It should be noted that ovarian volume and follicular number decrease with age, so standard criteria may not be applicable to women >40 years of age. Also, multifollicular ovaries may be observed during puberty, subsiding once the normal menstrual pattern is established. In one meta-analysis, the pooled sensitivity of AMH for diagnosis of PCOS was 0.78 (95% CI: 0.74 to 0.81) and pooled specificity was 0.87 (95% CI: 0.84 to 0.90). However, there was substantial heterogeneity between studies and optimal cut-off values have not been defined. Consider adolescents with only hyper-androgenism (and no irregular cycles) 'at risk' of PCOS and reassess later. Ultrasound and AMH levels are not recommended for diagnosis of PCOS in adolescents due to poor specificity in this age group. DIAGNOSIS 10 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Diagnosis Polycystic ovarian ultrasound From the collection of Dr M.O. Goodarzi; used with permission Hirsutism absent If hirsutism is not present, serum androgens should be measured to evaluate for hyper- androgenism. The most commonly measured androgens are total and free testosterone and dehydroepiandrosterone sulfate (DHEAS). Biochemical hyper-androgenism is best assessed DIAGNOSIS by calculated free testosterone, free androgen index, calculated bioavailable testosterone, or by high quality testosterone assays such as liquid chromatography tandem mass spectrometry or extraction/chromatography affinity immunoassays. If any of these are elevated, the diagnostic sequence is the same as when hirsutism is present. Levels >2 standard deviations above the mean qualifies as a positive test. Testosterone levels are difficult to measure in women; even assays using liquid chromatography mass spectrometry exhibit poor precision at the low levels characteristically found in women. Additionally, many laboratory reference ranges for androgens in women did not carefully exclude women with PCOS. Hyper-androgenaemia is present in 60% to 80% of women with PCOS: 70% have elevated free testosterone, 40% have elevated total testosterone, 25% have elevated dehydroepiandrosterone sulfate. In obese women, sex hormone-binding globulin levels are low, resulting in elevated free testosterone and often normal total testosterone. Androgen level tests should be performed in the follicular phase (in cycling women), in the morning, and at least 3 months after cessation of any hormonal therapies. An exception to these hormonal therapies is a cyclic progestin. This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 11 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Diagnosis If hirsutism is not present, all androgen levels are normal, and there is a history of infrequent/ reduced menstrual bleeding, an ovarian ultrasound or serum AMH measurement should be performed in adults. Combined with such a history, polycystic ovarian morphology allows a diagnosis of PCOS to be made (Rotterdam criteria only). Consider adolescents with only irregular cycles (and no hyper-androgenism) 'at risk' of PCOS and reassess later. Ultrasound and AMH levels are not recommended for diagnosis of PCOS in adolescents due to poor specificity. Levels of androstenedione or DHEAS may be checked if other androgens are normal, but these have lower specificity and DHEAS has greater age-associated decrease. Androstenedione measurement may increase the number of women identified as hyper-androgenaemic by 10%. The American College of Obstetricians and Gynecologists PCOS guideline suggests evaluating DHEAS is of little value except in cases of rapid virilization. Checking dehydroepiandrosterone is of little value. Tests in all women Thyroid-stimulating hormone, prolactin, and 17-hydroxyprogesterone should be measured in all women to exclude disorders that may resemble PCOS (thyroid dysfunction, hyperprolactinaemia, and 21-hydroxylase-deficient adrenal hyperplasia, respectively). However, low-level prolactin elevations (20-30 ng/mL) are common in PCOS without associated galactorrhoea or pituitary adenoma on imaging. In uncertain cases, elevated luteinising hormone (LH)/follicle-stimulating hormone (FSH) ratio may support a diagnosis of PCOS. LH pulses are abnormally elevated (frequency and amplitude), leading to increased serum LH levels and LH/FSH ratio >3 in only two-thirds of women with PCOS. LH/FSH ratio is elevated more often in lean women. This ratio is helpful only if positive, and is not diagnostic. Checking LH and FSH is also useful to rule out hypothalamic amenorrhoea (levels low) or perimenopause/ovarian failure (levels high). Given the high frequency of insulin resistance and metabolic syndrome in PCOS, an oral glucose DIAGNOSIS tolerance test and fasting lipid panel should be performed in all women at diagnosis to evaluate metabolic risk factors. Diabetes is defined as fasting glucose ≥7 mmol/L (126 mg/dL), or 2-hour glucose ≥11 mmol/ L (200 mg/dL). Prevalence of abnormal glucose tolerance (impaired fasting glucose, impaired glucose tolerance, or diabetes) is as high as 40% in women with PCOS. In one meta-analysis, the odds of prevalent impaired glucose tolerance was 3.3, and of prevalent diabetes 2.9, in women with PCOS. All women should be screened for impaired glucose tolerance with an oral glucose tolerance test. Those with normal glucose tolerance should be rescreened at least every 2 years. Those with impaired glucose tolerance should be screened annually for type 2 diabetes. Assessment of insulin resistance/hyperinsulinaemia is problematic, given variability in insulin assays and the need for population-specific normative ranges. However, insulin levels may be measured to give insight into whether insulin resistance is present. Fasting insulin >69 to 104 pmol/L (10-15 micro-units/mL) may suggest insulin resistance. During the oral glucose tolerance test, a peak insulin of 695-1042 pmol/L (100-150 micro- units/mL) may indicate mild insulin resistance, 1042-2084 pmol/L (150-300 micro-units/ 12 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Diagnosis mL) moderate insulin resistance, and >2084 pmol/L (300 micro-units/mL) severe insulin resistance. Fasting plasma glucose or haemoglobin A1c are less accurate than oral glucose tolerance testing, but may be considered as second-line alternatives if an oral glucose tolerance test cannot be performed. History and exam Key diagnostic factors presence of risk factors (common) Key risk factors include premature adrenarche or a family history of polycystic ovary syndrome. female of reproductive age (common) Symptoms typically start at the time of puberty. However, if oral contraceptives were begun at a young age, symptoms may be masked until therapy is stopped, which may delay the presentation and diagnosis. irregular menstruation (common) Irregular menses is a common manifestation of oligo- or anovulation, occurring in 75% of women with polycystic ovary syndrome (PCOS). Guidelines from the International PCOS Network define irregular menstrual cycles as follows: 45 days for those 1 to 3 years after breast development. Irregular menstruation is normal in the first year post menarche. Women with regular periods may also have anovulatory cycles. Up to 40% of hirsute regularly menstruating women have anovulatory cycles when further investigated. As women with PCOS age (i.e., >30 years), cycle length may shorten and some women may DIAGNOSIS experience regular cycles. infertility (common) Often a presenting complaint. hirsutism (common) Present in 60% of women with polycystic ovary syndrome. Hirsutism is the presence of terminal hairs (thick, pigmented) in androgen-dependent areas (upper lip, chin, chest, back, upper arm, shoulders, linea alba, peri-umbilical region, thigh, buttocks). Hirsutism can be quantified using the modified Ferriman-Gallwey score, with levels ≥4-6 indicating hirsutism. It is not to be confused with hyper-trichosis (diffuse vellus hairs). Some ethnic groups, particularly East Asians, are less prone to express hirsutism. It is important to ask about excess hair growth, because women often use methods of mechanical or local hair removal. Thus, the physical examination may not disclose hirsutism. This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 13 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Diagnosis Other diagnostic factors acne (common) May be masked by acne therapy. Acne is present in 15% to 25% of women with polycystic ovary syndrome (PCOS). Severe acne persisting beyond adolescence may be more indicative of PCOS. Acne is a non-specific feature; many women with acne will not have PCOS. overweight or obesity (common) Depending on culture and ancestry, 30% to 80% of women with polycystic ovary syndrome (PCOS) are overweight or obese, with central obesity (waist-to-hip ratio >0.85 or waist circumference >88 cm). Body mass index and waist circumference should be assessed in all women with PCOS. hypertension (common) Non-specific, but commonly seen. Blood pressure should be measured in all women with polycystic ovary syndrome. scalp hair loss (uncommon) The exact prevalence of alopecia in polycystic ovary syndrome (PCOS) is unknown, but may be as low as 5%. It is not a specific symptom, because many other disorders can cause alopecia. Typically, scalp hair loss in PCOS is at the vertex and crown, with relatively intact frontal hairline. Hair on the sides of the head may be preserved. oily skin or excessive sweating (uncommon) Hyper-hidrosis and/or seborrhoea may be a manifestation of hyper-androgenism. The exact prevalence of such symptoms in polycystic ovary syndrome is not known. acanthosis nigricans (uncommon) Usually subtle. Seen more often in obese women with polycystic ovary syndrome. This is a reflection DIAGNOSIS of hyperinsulinaemia. 14 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Diagnosis DIAGNOSIS Acanthosis nigricans involving the axilla of an obese white woman From the collection of Melvin Chiu, MD, UCLA; used with permission Acanthosis nigricans is dermal hyperplasia visible as brown or grey, velvety, occasionally verrucous, hyperpigmented areas over the nape of the neck, also the vulva, axillae, groin, umbilicus, sub- mammary areas, elbows, and knuckles. Skin tags are often found in the neck area also. In the US, it has been noted that obese black and Hispanic women tend to have clinical acanthosis nigricans. Other causes include diabetes, excess corticosteroids or growth hormone (endogenous or exogenous), nicotinic acid, or gastric adenocarcinoma. Risk factors Strong This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 15 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Diagnosis family history of PCOS First-degree female relatives of women with PCOS have a 20% to 40% prevalence of PCOS, significantly increased compared with the general population (prevalence 6% to 13%). PCOS appears to be inherited as a common, complex genetic condition. premature adrenarche Premature adrenarche (early onset of pubic/axillary hair and apocrine sweat gland development) is followed by development of PCOS in up to 50% of cases. obesity Multiple causality analyses using genetic data have consistently found that obesity causes PCOS. Childhood/adolescent adiposity may have a greater impact on PCOS risk than adulthood adiposity. On the other hand, having PCOS does not appear to increase the risk of obesity. Weak low birth weight Might predispose to development of hyper-androgenism later in life by predisposing to premature adrenarche and hyperinsulinaemia. One national registry-based cohort study found that being born small for gestational age as a risk factor for future PCOS was mediated by maternal obesity and smoking. fetal androgen exposure Daughters of women with congenital adrenal virilising disorders may develop features of hyper- androgenism. The fact that PCOS did not occur more frequently in females with a male co-twin than in females with a female co-twin argues against fetal androgen exposure as a major factor in the development of PCOS. Studies of umbilical cord blood of infants born to women with PCOS have yielded conflicting results, such as no elevation in androgen levels, or testosterone levels similar to male cord DIAGNOSIS blood. environmental endocrine disruptors Higher levels of bisphenol A have been observed in PCOS women compared with matched controls. Elevated bisphenol A in PCOS has been linked to insulin resistance and hyper- androgenism. It remains to be established whether such environmental factors are causative in PCOS. 16 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Diagnosis Investigations 1st test to order Test Result serum 17-hydrox yprogesterone >24 nmol/L (>800 ng/ dL) indicates adrenal Performed to exclude 21-hydroxylase-deficient non-classic (adult- hyperplasia onset) adrenal hyperplasia (NCAH). If the value is between 6 and 24 nmol/L (200 and 800 ng/dL), a level obtained 60 minutes after adrenocorticotrophic hormone stimulation is indicated to rule out the disorder. Stimulated values >30 nmol/ L (1000 ng/dL) (usually >45 nmol/L [1500 ng/dL]) occur when the woman has NCAH. serum prolactin elevation may suggest prolactinoma This test is performed to exclude hyperprolactinaemia, which may present with oligo- or anovulation. However, low-level prolactin elevations 870-1304 pmol/L (20-30 ng/mL or 20-30 micrograms/L) are common in polycystic ovary syndrome without associated galactorrhoea or pituitary adenoma on imaging. serum thyroid-stimulating hormone abnormal in thyroid disease Active thyroid dysfunction may present with oligo- or anovulation, or irregular and heavy menstrual bleeding. oral glucose tolerance test fasting glucose level between 5.6 and 6.9 Fasting glucose measurement, followed by glucose measurement 2 mmol/L (100 and 125 mg/ hours after administration of 75 g of glucose given orally. Prevalence of abnormal glucose tolerance (impaired fasting glucose, dL) is impaired fasting impaired glucose tolerance or diabetes) is as high as 40% in glucose; impaired glucose polycystic ovary syndrome (PCOS). In one meta-analysis, the odds tolerance is 2-hour glucose of 7.8 to 11.0 of prevalent impaired glucose tolerance was 3.3, and of prevalent mmol/L (140-199 mg/dL); diabetes 2.9, in PCOS. diabetes is defined as DIAGNOSIS All women should be screened for impaired glucose tolerance fasting glucose ≥7 mmol/ with an oral glucose tolerance test. Those with normal glucose L (126 mg/dL), or 2-hour tolerance should be re-screened at least every 2 years. Those with glucose ≥ 11 mmol/L (200 impaired glucose tolerance should be screened annually for type 2 mg/dL) diabetes. Assessment of insulin resistance/hyperinsulinaemia is problematic, given variability in insulin assays and the need for population-specific normative ranges. However, insulin levels may be measured to give insight into whether insulin resistance is present. A fasting insulin >69 to 104 pmol/L (10-15 micro-units/mL) may suggest insulin resistance. During the oral glucose tolerance test, a peak insulin of 695-1042 pmol/L (100-150 micro-units/mL) may indicate mild insulin resistance, 1042-2084 pmol/L (150-300 micro-units/mL) moderate insulin resistance, and >2084 pmol/L (300 micro-units/mL) severe insulin resistance. This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 17 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Diagnosis Test Result fasting lipid panel elevated total cholesterol, LDL-cholesterol, Dyslipidaemia is often observed in polycystic ovary syndrome triglycerides; low HDL- (PCOS). Assessment of fasting lipids has been cholesterol advocated for all women with PCOS. Treatment may be instituted if cardiovascular risk is increased, based on overall evaluation of risk factors. DIAGNOSIS 18 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Diagnosis Other tests to consider Test Result serum total and free testosterone elevated Elevation >2 standard deviations above the mean qualifies as a positive test. Many laboratory reference ranges for androgens in women did not carefully exclude women with polycystic ovary syndrome (PCOS). Testosterone levels are difficult to measure in women; even assays using liquid chromatography mass spectrometry exhibit poor precision at the low levels characteristically found in women. Hyper-androgenaemia is present in 60% to 80% of women with PCOS: 70% have elevated free testosterone, 40% have elevated total testosterone, 25% have elevated dehydroepiandrosterone sulfate. In obese women, sex hormone-binding globulin levels are low, resulting in elevated free testosterone and often normal total testosterone. Androgen level tests should be performed in the follicular phase (in cycling women), in the morning, and at least 3 months after cessation of any hormonal therapies. An exception to these hormonal therapies is a cyclic progestin. serum dehydroepiandrosterone sulfate (DHEAS) elevated May be done if other serum androgens are normal. Elevation >2 standard deviations above the mean qualifies as a positive test. Many laboratory reference ranges for androgens in women did not carefully exclude women with polycystic ovary syndrome (PCOS). Hyper-androgenaemia is present in 60% to 80% of women with PCOS: 70% have elevated free testosterone, 40% have elevated total testosterone, 25% have elevated DHEAS. DHEAS levels are the only elevated androgen in 10% of women with PCOS. The American College of Obstetricians and Gynecologists PCOS guideline suggests evaluating DHEAS is of little value except in cases of rapid virilisation. DIAGNOSIS serum androstenedione elevated May be done if other serum androgens are normal. Measurement may increase the number of women identified as hyper- androgenaemic by 10%. pelvic ultrasound ≥20 follicles in each ovary Polycystic ovaries are present in 75% of women with polycystic ovary measuring 2-9 mm in syndrome (PCOS), but are also seen in up to 25% of normal women diameter, and/or increased ovarian volume (≥10 mL) and women with other endocrinopathies such as congenital adrenal in either or both ovaries hyperplasia, hyperprolactinaemia, or hypothalamic amenorrhoea. (using endovaginal ultrasound at 8 MHz); endometrial lining >5 to 7 mm in thickness indicates endometrial thickening. If using older ultrasound technology or transabdominal ultrasound, focus on ovarian volume ≥10 mL in either ovary as a positive test This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 19 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Diagnosis Test Result Polycystic ovarian ultrasound From the collection of Dr M.O. Goodarzi; used with permission Transvaginal ultrasound, where appropriate, gives higher-resolution images of the ovaries than trans-abdominal ultrasound. Ovarian volume may be estimated as 0.5 x length x width x thickness. Ultrasound should be done in the early follicular phase (day 3-5) after a spontaneous or progestin-withdrawal-induced menstruation, or randomly in women with infrequent/reduced menstrual bleeding. If evidence of a dominant follicle (>10 mm) or a corpus luteum is seen, the ultrasound should be repeated at the next cycle. Polycystic ovarian morphology is a risk factor for ovarian hyperstimulation syndrome in women undergoing ovulation induction (with clomifene or gonadotrophins). Therefore, an ultrasound before ovulation induction may be useful. If endometrial thickening is found, an endometrial biopsy is indicated to determine whether endometrial hyperplasia or cancer is present. Routine ultrasound screening for endometrial thickness is not DIAGNOSIS recommended. It should be noted that ovarian volume and follicular number decrease with age, so standard criteria may not be applicable to women >40 years of age. Also, multi-follicular ovaries may be observed during puberty, subsiding once the normal menstrual pattern is established. The International PCOS Network guideline recommends against ultrasound for diagnosis of PCOS in adolescents due to poor specificity. serum anti-Mullerian hormone elevated May be considered as an alternative to pelvic ultrasound in adults. Not recommended for diagnosis of polycystic ovary syndrome (PCOS) in adolescents due to poor specificity in this age group. One meta-analysis reported a pooled sensitivity of 0.78 (95% CI: 0.74 to 0.81) and a specificity of 0.87 (95% CI: 0.84 to 0.90) for diagnosing PCOS. However, there was substantial heterogeneity between studies and optimal cut-off values have not been defined. 20 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Diagnosis Test Result basal body temperature monitoring biphasic pat tern indicates ovulation has occurred; Up to 20% of women suspected of having polycystic ovary syndrome flat pat tern indicates report regular menses. In such cases, investigation to document anovulation anovulation may be indicated. luteal phase progesterone measurement >6.4 to 25.4 nmol/L (>2-8 ng/mL) indicates Performed on day 20-24 of the menstrual cycle. ovulation has occurred Up to 20% of women suspected of having polycystic ovary syndrome report regular menses. In such cases, investigation to document anovulation may be indicated. serum LH and follicle-stimulating hormone (FSH) LH/FSH ratio >3 suggests PCOS LH pulses are abnormally elevated (frequency and amplitude), leading to increased serum LH levels and LH/FSH ratio >3 in only two-thirds of women with polycystic ovary syndrome (PCOS). LH/FSH ratio is elevated more often in lean women. This ratio is helpful only if positive, and is not diagnostic. Checking LH and FSH is also useful to rule out hypothalamic amenorrhoea (levels low) or perimenopause/ovarian failure (levels high). haemoglobin A1c or fasting plasma glucose fasting glucose level between 5.6 and 6.9 mmol/ Given the high frequency of insulin resistance and metabolic syndrome in polycystic ovary syndrome, testing should be performed L (100 and 125 mg/dL) is impaired fasting glucose; in all women at diagnosis to evaluate metabolic risk factors. Fasting plasma glucose or haemoglobin A1c are less accurate than haemoglobin A1c of oral glucose tolerance testing, but may be considered as second-line 39-47 mmol/mol (5.7% to alternatives if an oral glucose tolerance test cannot be performed. 6.4%) is consistent with prediabetes; diabetes is defined as fasting glucose ≥7 mmol/L (≥126 mg/dL), or haemoglobin A1c ≥48 mmol/mol (≥6.5%) DIAGNOSIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 21 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Diagnosis Differentials Condition Differentiating signs / Differentiating tests symptoms 21-hydrox ylase deficiency Partial deficiency of the 21- A morning, follicular-phase hydroxylase enzyme within 17-hydroxyprogesterone the cortisol biosynthetic level 800 ng/ precursors. dL) rules it in. Intermediate Clinical presentation may be values prompt cosyntropin indistinguishable from that of (adrenocorticotrophic PCOS. hormone) stimulation testing. Certain ethnic groups are Women with non-classic at risk: Yupik Eskimos, congenital adrenal Ashkenazi Jews, and hyperplasia always have a Hispanic, Italian, and stimulated (60 minutes) 17- Yugoslav women. hydroxyprogesterone value Very rare in African- >30 nmol/L (>1000 ng/dL) Americans. (usually >45 and 1500 and 28 years) women or those with increased central obesity. While adding metformin to clomifene seems to improve ovulation rates, the impact on live birth rate has been questioned. Other meta-analyses found clomifene plus metformin to increase pregnancy and live birth versus clomifene alone in clomifene-resistant women. Second-line treatment If these measures fail, injectable treatments such as gonadotrophins should be given. Gonadotrophins (human menopausal gonadotrophins [hMG]: luteinising hormone [LH] plus follicle-stimulating hormone [FSH]) directly act on the ovary, stimulating follicular recruitment and maturation. In women with PCOS who have anovulatory infertility and clomifene resistance, the International PCOS Network recommends that gonadotrophins are preferable to clomifene plus metformin, gonadotrophins alone are preferred to gonadotrophins plus clomifene, and either gonadotrophins or laparoscopic ovarian surgery can be offered. Treatment with gonadotrophins is associated with a high risk of multiple pregnancies (twins in 20% to 30%, triplets in 1% to 2%) and ovarian hyperstimulation syndrome (OHSS), especially if many follicles reach intermediate size or if serum estradiol is too high. Mild OHSS (abdominal distention, nausea, vomiting, diarrhoea) is common. Severe OHSS may cause extreme cystic ovarian enlargement (pain, haemorrhagic cysts, torsion), vascular hyperpermeability (ascites, hydrothorax, hypoproteinaemia, electrolyte disturbance, hemoconcentration, oliguria, pulmonary oedema), and, in the most severe cases, thrombosis (sometimes at unusual sites, e.g., subclavian or internal jugular vein) or thromboembolism. Close follow-up and careful dosing are required to avoid OHSS. In PCOS, lower doses of hMG are used because of the increased risk of OHSS compared with women without PCOS. FSH alone and hMG have similar rates of OHSS, pregnancy, and live birth. Polycystic ovarian morphology is a risk factor for OHSS. Therefore, ultrasound evaluation of the ovaries may assist in selecting the initial dose of gonadotrophins. The step-up and step-down approaches with FSH were compared in clomifene-resistant women with PCOS. The pregnancy rates did not differ, but the step-up approach had higher rates of ovulation and MANAGEMENT lower rates of OHSS. Another trial found a sequential step-up and step-down protocol to have higher pregnancy and lower miscarriage rates then either step-up or step-down protocols. Gonadotrophins are usually given as sole therapy; however, adding metformin might reduce the risk of ovarian hyperstimulation syndrome. Preliminary evidence suggests that taking metformin 28 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Management during ovulation induction with gonadotrophin, followed by timed intercourse or intrauterine insemination, might increase rates of pregnancy and live birth. Third-line treatment In the most difficult cases, in vitro fertilisation (IVF) or laparoscopic ovarian drilling is performed. Laparoscopic ovarian drilling (the use of electrocautery or laser to reduce the amount of functional ovarian tissue to reduce androgen production, also reduces inhibin production, allowing FSH to rise and stimulate ovarian aromatase) can restore ovulation and result in pregnancy rates of 25% to 65%. While there is no risk of hyperstimulation or multiple births with ovarian drilling, there is a risk of post-operative adhesion formation (much less than previous ovarian wedge resection techniques) and ovarian atrophy. One meta-analysis comparing laparoscopic ovarian drilling with medical induction of ovulation (including gonadotrophins, clomifene, letrozole, metformin, and others alone and in combination) in women with anovulatory PCOS who had clomifene resistance found a lower live birth rate with laparoscopic ovarian drilling; when the analysis was restricted to trials with a low risk of bias, the live birth rates were similar. Furthermore, in women with anovulatory PCOS who had clomifene resistance, laparoscopic ovarian drilling versus medical induction of ovulation was associated with similar rates of pregnancy and miscarriage but lower rates of multiple pregnancy and ovarian hyperstimulation syndrome. There is no conclusive evidence that laparoscopic ovarian drilling leads to diminished ovarian reserve or premature ovarian failure. Unilateral and bilateral ovarian drilling may have similar efficacy in clinical pregnancy and live birth rates. Ovarian drilling may be most effective in clomifene-resistant women, with BMI 20 years), and diabetes with vascular complications. Anti-androgens The Endocrine Society advises against anti-androgen monotherapy as initial therapy for hirsutism because of its teratogenic potential (unless women are on adequate contraception). For women who are not sexually active, have undergone permanent sterilisation, or are on long-acting reversible contraception, initial therapy with OCP or anti-androgens as monotherapy are both options. If monotherapy is to be used, the decision is tailored to the woman's needs, with a particular focus on adverse effects. Women with severe hirsutism or contraindications to hormonal contraception may need to be considered for treatment with anti-androgens. Anti-androgens are androgen receptor blockers (e.g., spironolactone, cyproterone) or 5-alpha-reductase inhibitors (e.g., finasteride). Anti-androgens (especially finasteride) should be avoided in pregnancy due to potential for ambiguous genitalia in male fetus. Flutamide is not recommended because of potential hepatotoxicity. Anti-androgens should be used for at least 6 months before judging efficacy. The maximal effect on hirsutism may take 9-12 months (compared with the effect on acne, which usually responds within 2 months). Acne is more responsive to therapy while alopecia is less responsive. Contraceptive measures are advisable given theoretical teratogenicity. In many cases, a combination of anti-androgen and oral contraceptive may be needed, particularly for hirsutism or severe acne. The combination has the added benefit of preventing pregnancy, while increasing efficacy by targeting two different processes: androgen production and androgen action. The MANAGEMENT Endocrine Society recommends monotherapy first line for hirsutism, and if symptoms remain after 6 months to add in an anti-androgen. Metformin 30 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Management The Endocrine Society advises against using insulin-lowering drugs for the sole indication of treating hirsutism. Meta-analyses suggest that metformin is associated with decreased testosterone and androstenedione levels and increased SHBG levels, with limited evidence of improvement in hirsutism. One Cochrane review also found metformin may be less effective in improving hirsutism compared with the OCP in women with PCOS who are overweight. Another meta-analysis of 51 studies concluded that metformin (alone or as adjuvant therapy) may improve acne scores. Adding metformin might improve results compared with monotherapy or dual therapy. Thus, for the specific goal of treating hyper-androgenism, it is best suited as add-on therapy to OCPs, anti- androgens, or OCPs plus anti-androgens. In one meta-analysis, metformin plus spironolactone was more effective for reducing BMI and serum androgen levels than metformin alone, but there was no significant effect on hirsutism score or gonadotrophin levels. The 2023 International PCOS Network guideline suggests that the combination of OCPs and metformin may be most beneficial in high risk metabolic groups, including women with BMI >30 kg/m², risk factors for diabetes, impaired glucose tolerance, or high-risk ethnic groups. To avoid gastrointestinal adverse effects, metformin should be taken with food and the dose titrated slowly over 4-6 weeks. Extended-release metformin has a slightly lower incidence of gastrointestinal adverse effects. Limited evidence suggests that metformin may promote weight loss, particularly at higher doses (>1500 mg/day) and with longer duration of therapy (>8 weeks). Long-acting gonadotrophin-releasing hormone (GnRH) analogues In very severe or refractory ovarian hyper-androgenism, GnRH analogues (e.g., leuprorelin) plus oestrogen yield profound suppression of gonadotrophins and suppress ovarian steroid synthesis. GnRH agonists are best combined with oestrogen (OCPs) to increase SHBG and protect bones from resultant hypo-oestrogenaemia (women on GnRH without oestrogen replacement may lose 4% to 8% trabecular bone after 6 months) and avoid severe vasomotor symptoms. With the oestrogen replacement, a progestin must also be given to protect the endometrium. Mechanical hair removal or topical therapy At any stage of therapy for hirsutism, mechanical or local hair removal is a useful adjunct to remove hairs that do not respond to medical therapy. To destroy terminal hair follicles, electrolysis (or laser, which works best with light skin and dark hair) is useful after ≥6 months of hormonal therapy has halted the appearance of new terminal hairs. Topical eflornithine slows growth of facial hair in 20% to 40% of women by 8 weeks. It should be discontinued if no results are noted by 4-6 months. For androgenetic alopecia, topical minoxidil treatment may be effective but must be used for several months. With both topical eflornithine and minoxidil, benefit subsides if the agent is discontinued. MANAGEMENT Not desiring current fertility: infrequent/reduced menstrual bleeding alone Anovulatory women with PCOS have chronic oestrogenisation without progesterone exposure, leading to risk of abnormal uterine bleeding, endometrial hyperplasia, and cancer. This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 31 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Management Therefore, treatments that induce ovulation (e.g., weight loss or metformin) or provide progesterone exposure (OCPs or a cyclic progestin) should be given to these women. Weight loss is the preferred treatment for overweight or obese women. The OCP or metformin is used if ineffective, or if weight is normal. If an OCP is not tolerated or desired by the patient, or if there are contraindications to an OCP, cyclic progestin should be given. A cyclic progestin is also used in refractory cases. Among the older OCPs, ethynodiol/ethinyl estradiol is considered low androgenic and may be useful if a larger dose of oestrogen is needed. This higher-oestrogen-dose pill may be able to induce menses in women with persistent amenorrhoea. Persistent amenorrhoea may indicate endometrial atrophy resulting from hyper-androgenism (thin endometrial width on ultrasound). The risk-benefit ratio must be carefully considered when using higher-dose pills. The International PCOS Network guidelines do not recommend a particular OCP over another. Not desiring current fertility: hyper-androgenic features plus infrequent/reduced menstrual bleeding These women are treated with a combined approach: Preferred treatment is weight loss (if overweight) plus OCPs Oral contraceptive plus an anti-androgen is used if this proves ineffective Long-acting GnRH analogue plus oestrogen is used for refractory cases Metformin may be used adjunctively for weight loss plus oral contraceptives, or for oral contraceptives plus anti-androgen For any stage of treatment, topical or mechanical hair removal may be added. MANAGEMENT 32 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Management Treatment algorithm overview Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer Acute ( summary ) with infertility and desiring fertility 1st weight loss 1st letrozole 1st clomifene adjunct met formin adjunct dexamethasone 1st met formin 2nd gonadotrophins adjunct met formin 3rd in vitro fertilisation adjunct met formin 3rd laparoscopic ovarian drilling MANAGEMENT This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 33 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Management Ongoing ( summary ) not desiring current fertility with hyper-androgenic 1st oral contraceptive pill features alone adjunct met formin adjunct mechanical hair removal or topical therapy 2nd anti-androgen adjunct met formin adjunct mechanical hair removal or topical therapy 2nd anti-androgen plus oral contraceptive pill adjunct met formin adjunct mechanical hair removal or topical therapy 3rd long-acting GnRH analogue plus oral contraceptive pill adjunct mechanical hair removal or topical therapy with infrequent/reduced 1st weight loss menstrual bleeding alone 2nd oral contraceptive pill 2nd met formin 3rd cyclic progestin with hyper-androgenic 1st weight loss features plus infrequent/ reduced menstrual bleeding plus oral contraceptive pill adjunct met formin adjunct mechanical hair removal or topical therapy 2nd anti-androgen plus oral contraceptive pill adjunct met formin MANAGEMENT adjunct mechanical hair removal or topical therapy 3rd long-acting GnRH analogue plus oral contraceptive pill 34 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Management Ongoing ( summary ) adjunct mechanical hair removal or topical therapy MANAGEMENT This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 35 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Management Treatment algorithm Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer Acute with infertility and desiring fertility 1st weight loss » The first-line and safest measure to restore ovulation is weight loss (in overweight or obese women). Weight loss alone (even as little as 5% to 7%) may restore ovulation in up to 80% of overweight or obese women (possibly by reducing hyperinsulinaemia and thus hyper-androgenism). Weight loss is also beneficial from a cardiovascular standpoint, and may improve subsequent pregnancy outcomes. Studies suggest dietary interventions, exercise, and/or behavioural coaching are effective for weight loss in polycystic ovary syndrome (PCOS), but no particular exercise or dietary composition (beyond caloric restriction) can be recommended over another. » If weight loss is unsuccessful, pharmacological ovulation induction therapy is recommended. » Guidelines recommend optimising pre- conception health and lifestyle for all women with PCOS, but weight loss is not recommended as first-line fertility treatment for normal-weight women with PCOS. In these women, letrozole or clomifene should be first-line. 1st letrozole Primary options » letrozole: 2.5 mg orally once daily for 5 consecutive days initially, increase by 2.5 mg/ day increments in subsequent cycles until ovulation is achieved, maximum 7.5 mg/day » The International PCOS Network and American College of Obstetricians and Gynecologists guidelines recommend letrozole as the first-line option for medical treatment of infertility in women with PCOS. Increasing data suggest that letrozole improves ovulation, pregnancy, and live birth rates MANAGEMENT compared with clomifene. However, the use of letrozole may be off-label in some countries, and some guidelines recommend clomifene as the preferred option. 36 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved. Polycystic ovary syndrome Management Acute » The Pregnancy in Polycystic Ovary Syndrome II trial (PPCOS II, sample size 750) found that letrozole was superior to clomifene in the live birth rate. Meta-analyses of randomised controlled trials have found letrozole to be superior to clomifene and similar to laparoscopic ovarian drilling for pregnancy and live birth. Rates of miscarriage, ovarian hyperstimulation syndrome, and multiple pregnancies appear to be similar between letrozole and clomifene. 1st clomifene Primary options » clomifene: 50 mg orally once daily for 5 consecutive days initially, increase by 50 mg/ day increments in subsequent cycles until ovulation achieved, maximum 150 mg/day » Clomifene is a non-steroidal anti-oestrogen that inhibits oestrogen negative feedback on the hypothalamus/pituitary, which in turn leads to an increase in follicle-stimulating hormone secretion that may allow follicular maturation and ovulation. » A very commonly used fertility treatment and effective in achieving pregnancy. Increasing data suggest that letrozole improves ovulation, pregnancy, and live birth rates compared with clomifene. The International PCOS Network and American College of Obstetricians and Gynecologists guidelines recommend letrozole as the first-line option for pharmacological treatment of infertility in women with PCOS. However, use of letrozole may be off-label in some countries, and some guidelines recommend clomifene as the preferred option. » Up to 25% of patients will have clomifene resistance due to ovarian unresponsiveness. There is a 5% to 10% risk of multiple pregnancy. In a clinical trial comparing clomifene, metformin (and clomifene plus metformin), multiple birth occurred in 6% of the clomifene group and 0% of the metformin group (and in 3.1% in the clomifene plus metformin group). » A meta-analysis found that compared with early follicular phase administration of clomifene, MANAGEMENT administration during the late luteal phase resulted in a higher total number of follicles, yet rates of ovulation and pregnancy were similar. adjunct met formin This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Feb 09, 2024. BMJ Best Practice topics are regularly updated and the most recent version of the topics 37 can be found on bestpractice.bmj.com. Use of this content is subject to our disclaimer (. Use of this content is subject to our). © BMJ Publishing Group Ltd 2024. All rights reserved.  Polycystic ovary syndrome Management Acute Treatment recommended for SOME patients in selected patient group Primary options » metformin: 500 mg orally (immediate- release) three times daily, or 850-1000 mg orally (immediate-release) twice daily; 1500-2000 mg orally (extended-release) once daily » If three treatment cycles of clomifene have failed, it is reasonable to add metformin. Some studies, but not all, suggest that adding metformin to clomifene may be efficacious if clomifene alone is unsuccessful. It is also reasonable to start with clomifene plus metformin rather than either agent alone as treatment of anovulatory infertility. The 2023 International PCOS Network guideline suggests clomifene plus metformin is preferred to clomifene alone. » A Cochrane review concluded that clomifene plus metformin results in a 60% higher pregnancy rate compared with clomifene alone, but data for live birth rates are inconclusive. Another meta-analysis comparing clomifene plus metformin to clomifene alone found the combination yielded a 28% higher clinical pregnancy rate but no differences in live birth rate. However, in two randomised trials, clomifene was similar in pregnancy or live birth rate to clomifene plus metformin. In one of these trials, metformin did not affect the dose of clomifene needed to achieve ovulation. In the other trial, sub- group analysis found metformin efficaciou