Polycystic Ovary Syndrome (PCOS) and Menstrual Irregularities - PDF

Polycystic Ovary Syndrome and Menstrual Irregularities CMS250 Dr. Zeynep Uraz, ND January 11th, 2024 Learning Outcomes Interpret the complexity of Polycystic Ovary Syndrome (PCOS), its incidence among reproductive age women, and its variable clinical presentation, including gynecologic, dermato...

Polycystic Ovary Syndrome and Menstrual Irregularities CMS250 Dr. Zeynep Uraz, ND January 11th, 2024 Learning Outcomes Interpret the complexity of Polycystic Ovary Syndrome (PCOS), its incidence among reproductive age women, and its variable clinical presentation, including gynecologic, dermatologic, and metabolic manifestations. Appraise the association between PCOS and metabolic syndrome, insulin resistance, obesity, and the long- term health risks, including type 2 diabetes mellitus, cardiovascular disease, endometrial hyperplasia, cancer, and perinatal complications, and the significance of evaluating blood pressure, lipid levels, and glucose tolerance in patients with PCOS. Analyze the diagnostic criteria for PCOS, including the Rotterdam criteria, and the significance of ultrasonography, laboratory tests, and imaging studies in diagnosing PCOS. Evaluate the clinical and biochemical evidence of hyperandrogenism in PCOS, and the significance of measuring serum FSH, estradiol, prolactin, TSH, lipid profiles, and glucose. Learning Outcomes Differentiate other potential causes of anovulation in reproductive years, the differential diagnosis of PCOS, and the importance of excluding other disorders that mimic its clinical features. Critique the concept of functional ovarian hyperandrogenism (FOH) and its relation to PCOS. Synthesize how to perform a targeted history and physical examination for patients with suspected or known PCOS, and how to screen for comorbidities associated with PCOS, such as depression and obstructive sleep apnea. Assess the importance of collaboration and communication among the interprofessional team in managing patients with PCOS, as well as the impact of PCOS on a woman’s self-image, quality of life, and reproductive health. Investigate the history of PCOS, its various names, and the diagnostic criteria proposed by different organizations and guidelines. What is PCOS? The most common endocrine disorder in reproductive age people with uterus/ovaries. Characterized by: irregular menstrual periods, high androgen levels and polycystic ovaries. Condition: Epidemiology Prevalence 5-15%, greater than 20% incidence and prevalence in overweight and obese populations Condition: Epidemiology Demographics Race/ethnicity Symptoms of androgen excess and metabolic dysfunction may vary among ethnicities, PCOS incidence may also vary across ethnicities. Risk factors 70% hereditary, though environment is a fundamental component in the expression of these genes, and the development and progression of the disease. History of PCOS 1935 - was originally described as a phenomenon in by Stein and Leventhal 1990 – National Institute of Health (NIH) proposed the first criteria for diagnosis 2003 – Rotterdam Criteria for diagnosis established by European Society for Human Reproduction and Embryology and the American Society of Reproductive Medicine Clinical Presentation and health risks Interpret the complexity of Polycystic Ovary Syndrome (PCOS), its incidence among reproductive age women, and its variable clinical presentation, including gynecologic, dermatologic, and metabolic manifestations. Appraise the association between PCOS and metabolic syndrome, insulin resistance, obesity, and the long-term health risks, including type 2 diabetes mellitus, cardiovascular disease, endometrial hyperplasia, cancer, and perinatal complications, and the significance of evaluating blood pressure, lipid levels, and glucose tolerance in patients with PCOS. Clinical Presentation Menstrual Dysfunction Metabolic syndrome and Hyperandrogenism cardiovascular disease Insulin resistance Endometrial Neoplasia Dyslipidemia Infertility Obesity Complications in pregnancy Obstructive Sleep Apnea Psychological health Health Risks associated with PCOS Short term: Long term: Obesity Endometrial cancer Infertility Type 2 Diabetes mellitus Obstructive sleep apnea Cardiovascular disease Irregular menses Endometrial hyperplasia Depression/anxiety Abnormal lipid levels Non-alcoholic fatty liver disease Hirsutism/acne/androgenic alopecia Insulin resistance/acanthosis nigricans Pregnancy-related complications Menstrual Dysfunction Menstrual dysfunction= oligomenorrhea, anovulation, and/or heavy menstrual bleeding Lack of ovulation → lack of progesterone production by corpus luteum → constant estrogen exposure → constant stimulation of the endometrium Instability of the thickened endometrium can lead to unpredictable bleeding Heavy menstrual bleeding often leads to iron deficiency anemia Menstrual Dysfunction Menstrual dysfunction is common and normal at menarche By mid-adolescence, regular ovulatory cycles are usually established In adolescents with PCOS irregularity continues Menstrual intervals 90 days anytime after menarche merits consideration for evaluation Health Risk: Endometrial hyperplasia and cancer Endometrial hyperplasia (EH): precancerous condition in which there is irregular thickening of the endometrium (uterine lining). Anovulation causes prolonged exposure of the endometrium to estrogen, without the regular exposure of progesterone. This leads to an increase risk of endometrial hyperplasia. Obesity and T2DM are also independent risk factors for endometrial cancer. Women with PCOS have a 3.5 fold increase risk of endometrial cancer. Health Risk: Endometrial hyperplasia and cancer In women with PCOS withdrawal bleeds should be medically induced at least every 3-4 months. Oral contraceptive pills and long-acting progestin only methods (IUD, etc) reduce the risk of endometrial cancer. Transvaginal US can be used to measure endometrial thickness in women without withdrawal bleeds but routine screening is not recommended (Endocrine Society). Endometrial assessment is done in any woman older than 45 years with abnormal uterine bleeding or younger than 45 with a history of unopposed estrogen. Hyperandrogenism Clinical manifestation: acne, hirsutism, androgenic alopecia. Does *not* present with signs typical of virilization: deepening voice, increased muscle mass, clitoromegaly. If these are present, look for androgen producing tumour. Hirsutism Coarse, dark, terminal hair distributed in a male pattern. Typically begins in late adolescence or early 20s. PCOS is the cause of 70-80% of all hirsutism cases. Most commonly on the upper lip, chin, sideburns, chest and linea alba. Racial and ethnic differences exist in the concentration of androgen sensitive hair follicles. E.g. Mediterranean women have a higher concentration than Asian women. Acne Acne is common in adolescence. However persistent, severe, or late onset acne should raise suspicion for PCOS or other conditions of androgen excess. In women with androgen excess overstimulation with androgens elevates sebum production which leads to inflammation and comedone production. Androgenic Alopecia Female pattern androgenic alopecia is less common in PCOS Hair slowly thins at the crown, but the frontal hairline remains intact Alopecia can also be caused by other illness and alopecia should be evaluated for thyroid dysfunction, iron-deficiency anemia Clinical Manifestation: Insulin Resistance People with PCOS display greater degrees of insulin resistance and compensatory hyperinsulinemia. Associated with metabolic and reproductive abnormalities (menstrual dysfunction). Is a major contributor to hyperandrogenism. Clinical manifestation is subtle. Health Risk: Insulin Resistance This impacts both obese and “lean” women with PCOS (greater degree of insulin resistance compared to age-matched controls). Insulin resistance is associated with type 2 diabetes mellitus, hypertension, dyslipidemia and cardiovascular disease. IR is of the fundamental underlying mechanisms of long-term health risks of PCOS. Dyslipidemia Prevalence of dyslipidemia is near 70% in women with PCOS. Most commonly: Increased low-density lipoprotein (LDL) and triglycerides Elevated total cholesterol: high density lipoprotein (HDL) ratios Low HDL levels May raise cardiovascular disease risk in women with PCOS Obesity Women with PCOS are more likely to be obese, especially centrally obese. Central obesity is an independent risk factor for cardiovascular disease and predicts insulin resistance. Obstructive Sleep Apnea (OSA) In the general population OSA is related to central obesity. In one meta-analysis 35% of women with PCOS had OSA, especially obese women with PCOS. In addition to just weight, some metabolic factors may be involved, as women with PCOS have a higher risk of OSA compared to weight-matched controls. Metabolic Syndrome Metabolic syndrome is characterized by: insulin resistance, obesity, dyslipidemia and hypertension Women with PCOS have an increased risk of metabolic syndrome compared to age-matched controls Prevalence is 45% compared to 4% in age-adjusted controls. Metabolic syndrome begins earlier in women with PCOS Cardiovascular disease Small studies suggest a higher relative risk of myocardial infarction and cardiovascular disease. People with PCOS have a 7-fold increased risk of myocardial infarction compared to age-matched controls. Risk is greatest in post-menopause. Infertility Is more common in women with PCOS, caused by anovulatory cycles. Endocrine society guidelines recommend screening for anovulation, even in people with PCOS with eumenorrhea (who are trying to get pregnant). This can be measured with mid- luteal phase serum progesterone. Complications in pregnancy Higher rate of early miscarriage (30-50%) compared to a baseline rate of 15% May only be higher than baseline in obese women with PCOS. Higher rate of gestational diabetes (also in normal weight women with PCOS, but BMI still associated with the likelihood and severity) For those using ovulation induction medications to conceive, higher rate of multifetal gestation. Pregnancy-related health risks Higher rate of early miscarriage (related to weight, higher prevalence in obese people with PCOS) Gestational diabetes (increased in normal weight people with PCOS, but even greater risk with elevated BMI) Pregnancy-induced hypertension Preterm birth For those who use ovulation-induction medications to conceive, there is higher risk of multifetal gestation. Psychological health Conditions such as anxiety, depression, eating disorders and negative body image are more prevalent in people with PCOS. Screening for depression and anxiety is recommended. Living with PCOS Diagnostic Criteria Analyze the diagnostic criteria for PCOS, including the Rotterdam criteria, and the significance of ultrasonography, laboratory tests, and imaging studies in diagnosing PCOS. Diagnostic Criteria Rotterdam criteria established in 2003 Meet two of the three criteria: Chronic anovulation Clinical or biochemical hyperandrogenism Polycystic ovarian morphology AND the exclusion of related disorders such as thyroid dysfunction, nonclassic congenital adrenal hyperplasia (NCAH), hypogonadotropic hypogonadism (hypothalamic amenorrhea), premature ovarian insufficiency, hyperprolactinemia.  Other organizations Criteria for Diagnosis of PCOS National Institutes of Health criteria, 1990 Rotterdam criteria, 2003 Androgen Excess & PCOS Society, 2009 Clinical Finding (must have both of the findings marked below) (must have any 2 of the findings marked below) (must have A, plus either B or C) Hyperandrogenism* X X A Oligomenorrhea X X B Polycystic ovaries X C PCOS = polycystic ovary syndrome * = clinical or biochemical evidence of excess androgen Menstrual dysfunction Irregular menstrual cycles are defined as: Normal in the first year post menarche as part of the pubertal transition > 1 to < 3 years post menarche: < 21 or > 45 days > 3 years post menarche to perimenopause: < 21 or > 35 days or < 8 cycles per year > 1 year post menarche > 90 days for any one cycle Primary amenorrhea by age 15 or > 3 years post thelarche (breast development) When irregular menstrual cycles are present a diagnosis of PCOS should be considered and assessed. Clinical or biochemical hyperandrogenism Diagnosis can be made based on clinical or biochemical evidence. Clinical manifestations are hirsutism, acne, and/or androgenic alopecia. In contrast, increased muscle mass, voice deepening and clitoromegaly are signs of exposure to greater levels of androgens and are not signs of PCOS. This usually reflects an androgen producing tumour of the ovary or adrenal gland. Clinical or biochemical hyperandrogenism Hirsutism: coarse, terminal hair distributed in a male pattern. Begins in late adolescence or early 20s. Hair follicle transforms to a terminal hair follicle with exposure to testosterone. This occurs in androgen sensitive areas. Upper lip, sideburns, chin, chest, linea alba and lower abdomen.  Assessing Hirsutism Ferriman-Gallwey Score Score from 1-4 in 9 areas Hirsutism is defined by a score >4-6 Far-East Asians have lower density of hair follicles AE-PCOS society suggests a threshold value of >3 in this population Ask about self-treatment Clinical hyperandrogenism Acne: mild to moderate acne vulgaris is a frequent clinical finding adolescents Moderate to severe, persistent or late-onset acne should raise concern for androgen excess/PCOS. Clinical hyperandrogenism Female androgenic alopecia: hair slowly diffuses at the crown but frontal hairline is preserved Less common finding than hirsutism and acne Biochemical hyperandrogenism Elevated free testosterone is found in 70-80% of women with PCOS. Elevated DHEA-S is found in 25-65% of women with PCOS. Should measure total and free testosterone. If a patient meets the clinical criteria for hyperandrogenism, biochemical androgens do not need to be assessed. Cannot be reliably assessed in people taking combined oral contraceptive pill (COCP) or for 3 months after discontinuing COCP. Polycystic ovarian morphology (PCOM) Most accurately detected by transvaginal ultrasound (TVUS) Rotterdam criteria (2004) suggest PCOM cutoff is at least 12 follicles (”cysts”) measuring 2-9mm in the whole ovary or ovarian size > 10ml Improvements in US technology have led to updated guidelines AE and PCOS society – 25 follicles (2-9mm) in the whole ovary Anti-Mullerian hormone (AMH) for determining diagnosis of PCOS when US is not available. AMH is a measure of ovarian reserve (follicle count). Polycystic ovarian morphology (PCOM) Follicle number per ovary declines over the reproductive lifespan There is no definitive criteria for PCOM in adolescents, therefore US assessment of ovaries is not recommended Ruling out related disorders Thyroid dysfunction Routine exclusion of thyroid dysfunction in people with signs of hyperandrogenism may be of limited value. However, since thyroid dysfunction is relatively common in reproductive age women, routine screening should be performed. Test: TSH Nonclassic Congenital Adrenal Hyperplasia (NCAH) A genetic disorder (autosomal recessive) that causes deficiency of 21-hydroxylase enzyme function Causes androgen excess and can clinically resemble PCOS Test: basal morning 17-OH-progesterone Hypogonadotropic hypogonadism Hypogonadotropic hypogonadism (HH) or functional hypothalamic amenorrhea. Suppression of the hypothalamic-pituitary-ovary (HPO), resulting in suppression of GnRH secretion, FSH and LH secretion → suppression of estrogen from ovaries Test: estradiol (E2), follicle stimulating hormone (FSH). (both low) Premature ovarian insufficiency (failure) Premature ovarian insufficiency (POI) is characterized by early loss of ovarian reserve and ovarian function (before the age of 40). Test: estradiol (E2) (low), follicle stimulating hormone (FSH) (high). Hyperprolactinemia High prolactin levels can cause oligo-ovulation, needs to be ruled out as a cause of menstrual dysfunction There are many potential causes of hyperprolactinemia – some physiologic like pregnancy, lactation, nipple stimulation, stress. Some pathologic: pituitary adenoma (prolactin-secreting), acromegaly. Test: Prolactin (caveat: hyperandrogenism → prolactin levels in the upper normal limit or slightly above normal). Other disorders If clinically suspected: Cushing’s syndrome Androgen secreting neoplasia High dose exogenous androgens Learning Outcomes Differentiate other potential causes of anovulation in reproductive years, the differential diagnosis of PCOS, and the importance of excluding other disorders that mimic its clinical features. Differential Diagnosis: anovulation Secondary amenorrhea In reproductive-aged women: First rule out pregnancy (most common cause) Ovarian diseases (40%) PCOS (30%) Premature ovarian failure (10%) Hypothalamic dysfunction (35%) Stress (10-21%) Weight loss/disordered eating (15-54%) Differential Diagnosis: anovulation Secondary amenorrhea In reproductive-aged women: Pituitary disease (19%) Prolactin secreting tumour (17%) Empty sella syndrome (1%) Sheehan’s syndrome (1%) Adrenocorticotropic hormone secreting tumor (