Polycystic Ovary Syndrome (PCOS) PDF

Polycystic Ovary Syndrome Pathophysiology and Long-Term Complications BMS250 Zeynep Uraz, ND 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. Conditi...

Polycystic Ovary Syndrome Pathophysiology and Long-Term Complications BMS250 Zeynep Uraz, ND 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 PCOS: The most common endocrine disorder in reproductive- age people with uterus/ovaries Prevalence 5-15%, closer to 20% in overweight and obese populations PCOS Clinical presentation varies significantly, making the diagnosis and management challenging. Underlying pathophysiology includes hyperandrogenism, ovulatory dysfunction, polycystic ovaries, and insulin resistance. Psychological manifestations include anxiety and depression, poor self image. Can have adverse health consequences throughout the lifespan (infertility, metabolic and cardiovascular health). Lower quality and satisfaction of life. NDs can play an important role (patient education, prevention, diet and lifestyle support). Hormonal Imbalances Pathophysiology is complex but important to understand for management of this condition. Three underlying mechanisms: · 3 Inappropriate gonadotropin secretion Insulin resistance with hyperinsulinemia Excessive androgen production Pathophysiology of polycystic ovary syndrome. FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone; T2DM = type 2 diabetes mellitus; U/S = ultrasound. Reprinted with permission from Rotstein A, Srinivasan R, Wong E, et al. McMaster Pathophysiology Review. http://www.pathophys.org/pcos/. Accessed June 9, 2018. Citation: Chapter 11 Polycystic Ovary Syndrome, O'Connell M, Smith JA. Women's Health Across the Lifespan, 2e; 2019. Available at: https://accessmedicine.mhmedical.com/content.aspx?sectionid=213570437&bookid=2575&Resultclick=2 Accessed: December 27, 2023 Copyright © 2023 McGraw-Hill Education. All rights reserved Causes and Contributing Factors of PCOS A definitive cause has not been established Genetic component (autosomal dominant? Polygenic?) Genetic and environmental interactions Exposure to fetuses to high androgen levels? ↳ Exogenous or endogenous Pathophysiology of PCOS Hormonal Imbalances Pathophysiology is complex but important to understand for management of this condition. Three underlying mechanisms: Inappropriate gonadotropin secretion Insulin resistance with hyperinsulinemia Excessive androgen production Citation: CHAPTER 18 Polycystic Ovarian Syndrome and Hyperandrogenism, Hoffman BL, Schorge JO, Halvorson LM, Hamid CA, Corton MM, Schaffer JI. Williams Gynecology, 4e; 2020. Available at: https://accessmedicine.mhmedical.com/content.aspx?sectionid=241010058&bookid=2658&Resultclick=2 Accessed: January 02, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved Production of androgens and estrogen  Altered gonadotropin secretion Altered gonadotropin-releasing hormone (GnRH) secretion pulsatility leads to an & increase in LH hormone secretion from the pituitary (compared to FSH secretion). Normally, GnRH leads to pulsatile secretion of FSH and LH (every 60-90 min). FSH – stimulates growth of ovarian follicles LH – stimulates ovulation and ovarian hormone production In PCOS- increase in GnRH pulsatility leads to an increase in LH pulse frequency and amplitude but FSH remains the same. -- This often leads to a higher LH:FSH ratio (above 2:1), which is common but not diagnostic in PCOS S - 5 LH → stimulates ovarian androgen production Lower FSH → reduction in aromatase activity, less conversion of testosterone to estrogen in the granulosa cells Altered gonadotropin secretion A dominant follicle does not develop, because LH secretion occursE before a dominant follicle develops Several immature follicles exist in the ovary, and usually, causes - difficulty ovulating Therefore, there is no luteal phase, and no progesterone is produced, leaving estrogen unopposed → endometrial neoplasia risk - Increased LH production leads to an increase in steroid hormone production in the ovary → excess androgen production  Elevated androgens and estrogens Increased androgen levels contribute to dyslipidemia and clinical signs (hirsutism and acne) Elevated serum androgens are peripherally converted to W estrogen in the adipose tissue (this phenomenon is augmented in obese people) * Normally, estrogen levels fluctuate throughout the cycle, - however this stable increased level of estrogen impacts the feedback loop at the hypothalamus and pituitary Elevated androgens and estrogens Chronically elevated estrogens → ongoing endometrial cell stimulation and an increase risk of endometrial hyperplasia The adrenal gland can also contribute to increased circulating - - androgens Insulin resistance and hypersecretion leads to follicular atresia - E Death of follicles Insulin Resistance Disruptions of Glucose Homeostasis Insulin resistance → hyper-secretion of insulin (maintaining normal blood glucose levels) → mildly elevated blood glucose levels (impaired glucose tolerance/pre-diabetes) → Diabetes  Insulin Resistance People with PCOS display greater insulin resistance and compensatory hyperinsulinemia IR = reduced glucose uptake from target cells (mostly muscle) in response to insulin Leads to compensatory hyperinsulinemia → to maintain normal blood sugar levels Both lean and overweight/obese people with PCOS are found to D have more IR than no—PCOS weight-matched controls Insulin Resistance IR has significant consequences Insulin stimulates the release of FSH and LH from the pituitary Comme Increases the release of androgens from the theca cells Decreases the production of SHBG in the liver → increased circulating androgens ↳ Sex hormone binding globulin Associated with T2DM, hypertension, dyslipidemia, and cardiovascular disease IR is responsible for many of the long term health consequences of PCOS (though many are multi-factorial) Insulin Resistance Therapies that target the reduction of insulin resistance have shown to decrease menstrual dysfunction, androgen concentrations, and improve metabolic profiles. Androgens Are stimulated by both elevated LH and insulin D A Primarily produced in the ovarian theca cells (testosterone and - androstenedione) · 3 Elevated free testosterone levels are noted in 70-80% with PCOS * Elevated DHEAS (an androgen) are noted in 25-65% of people with PCOS  Sex-hormone binding globulin Sex hormone binding globulin (SHBG), produced in the liver, - binds most sex hormones. The non-bound hormones are free to circulate and are biologically active. (1%) The production of SHBG is suppressed by insulin production Due to less circulating SHBG, more androgens are unbound and free to circulate and bind with end-organ receptors (hair * follicles, sebaceous glands → acne) → clinical - hyperandrogenism - Androgens Low SHBG have also been linked to impaired glucose tolerance and risk of developing T2DM The mechanism is not fully understood Also associated with increased risk of gestational diabetes Anovulation Mechanisms are multifactorial and not fully understood Altered GNRH pulsatility is implicated IR plays a role, as patients with oligo-ovulation who are treated with insulin sensitizers such as metformin can resume normal ovulatory cycles & Theca cells Androgens produced by the large number of antral follicles may also contribute to oligo/anovulation Signs, Symptoms and Long Term Health Consequences Williams Gynecology, 4e >Polycystic Ovarian Syndrome and Hyperandrogenism Barbara L. Hoffman, John O. Schorge, Lisa M. Halvorson, Cherine A. Hamid, Marlene M. Corton, Joseph I. Schaffer+ TABLE 18-2Consequences of Polycystic Ovarian Syndrome Short-term consequences Obesity Infertility Sleep apnea Irregular menses Depression/anxiety Abnormal lipid levels Non-alcoholic fatty liver disease Hirsutism/acne/androgenic alopecia Insulin resistance/acanthosis nigricans Long-term consequences Diabetes mellitus Endometrial cancer Cardiovascular disease Date of download: 01/03/24 from AccessMedicine: accessmedicine.mhmedical.com, Copyright © McGraw Hill. All rights reserved. Obesity Women with PCOS are more likely to be obese (elevated BMI and waist to hip ratio) Android / central pattern of obesity is more common → independent risk factor for insulin resistance and cardiovascular disease Obesity exacerbates IR → which plays a central role in the pathogenesis of PCOS (can worsen hyperandrogenism, acanthosis nigricans, menstrual dysfunction). Infertility Results from anovulatory cycles in PCOS In women with infertility secondary to anovulation, PCOS is a common cause Menstrual Dysfunction Can include amenorrhea, oligomenorrhea and heavy menstrual bleeding (leading to iron-deficiency anemia). Result of anovulation → lack of progesterone production Chronic unopposed estrogen exposure leads to chronic exposure of the endometrium → instability of thickened - - endometrium can lead to unpredictable bleeding - Menstrual Dysfunction Oligomenorrhea (less than 9 menstrual periods in a year) and amenorrhea (absence of menses for 3 or more months) usually - - begins with menarche in people with PCOS Most adolescents at post-menarche have irregular cycles due to the immaturity of the hypothalamic-pituitary-ovarian axis * Menstrual intervals 45 days > 2 years after menarche or an interval >90 days at any time warrants further evaluation 31 Most gynecologists will delay the diagnosis of PCOS until late adolescence or early adulthood, with careful monitoring Menstrual Dysfunction As people with PCOS age, regular cycles may resume (due to - lower antral follicle count, and decrease in follicular androgen - production) Obstructive Sleep Apnea (OSA) OSA is related to central obesity (in the general population) One large study (meta-analysis) found that 35% of women with PCOS had OSA, obese individuals were especially likely to have OSA But metabolic changes in PCOS are also likely contributory Women with PCOS are more likely than weight-matched controls to have OSA Dyslipidemia Classic pattern in people with PCOS is high levels of low- density lipoprotein (LDL) and triglycerides Lower high-density lipoprotein (HDL) and elevated total cholesterol:HDL ratio. Prevalence of dyslipidemia in PCOS is close to 70% * This pattern of lipids is associated with atherogenic changes and an increase risk of cardiovascular disease Hyperandrogenism · 3 Hirsutism Acne Alopecia Signs of rapid increases in androgens such as increased muscle mass, deepening voice, and cliteromegaly are *NOT* typical of PCOS Should be a sign for prompt investigation of androgen secreting tumor  Hirsutism Elevated androgen levels determine the type and distribution of hair Within the hair follicle, testosterone is converted by 5 alpha reductase to dihydrotestosterone (DHT). While both testosterone and DHT convert short vellus hair to terminal hair, DHT is more effective. ↑ Conversion of the hair follicle is permanent and irreversible. Only follicles in androgen sensitive areas respond in this manner. Hirsutism Most commonly affected areas are the upper lip, chin, sideburns, chest, and linea alba of the lower abdomen. There is no difference between sexes in the concentration of hair follicles, however racial and ethnic differences exist. Mediterranean individuals have a greater concentration than Northern Europeans, and a much higher concentration than Asians. This impacts the clinical presentation of hyperandrogenism.  Alopecia Less common finding in people with PCOS Caused by an excess of 5 alpha reductase activity in the hair & follicle → rise in DHT levels z Terminal hairs that are not dependent on androgens transform to a vellus hair follicle – leading to alopecia Alopecia should always be investigated as it can be caused by other chronic/serious diseases (thyroid dysfunction, chronic illness, or anemia). Androgenic effects on the pilosebaceous unit. In some hair-bearing areas, androgens stimulate sebaceous glands, and vellus follicles (A) are converted to terminal follicles (B), leading to hirsutism. Under the influence of androgens, terminal hairs that were not previously dependent on androgens (C) revert to a vellus form and balding results (D). Citation: CHAPTER 18 Polycystic Ovarian Syndrome and Hyperandrogenism, Hoffman BL, Schorge JO, Halvorson LM, Hamid CA, Corton MM, Schaffer JI. Williams Gynecology, 4e; 2020. Available at: https://login.ccnm.idm.oclc.org/ Accessed: January 04, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved Acne Mild to moderate acne vulgaris is a common finding in adolescents. Elevated androgen levels have been reported in 80% of women with severe acne, 50% of women with moderate acne, and 33% with mild acne. Women with moderate to severe acne have an increased prevalence 52-83% of polycystic ovarian morphology on US evaluation. Acne Four factors involved in pathogenesis of acne: is 1. Blockage of the follicular opening by hyperkeratosis 2. Sebum overproduction 3. Proliferation of commensal bacteria (Propionibacterium acnes) 4. Inflammation Testosterone is converted to DHT in the sebaceous glands This leads to increase in sebum formation leading to inflammation and comedone formation Inflammation leads to scarring Acne Treatment should target: Minimizing inflammation decreasing keratin production lowering colonization of P. acnes reducing androgen levels to diminish sebum production Insulin resistance Assessing insulin resistance in clinical setting is difficult Insulin sensitivity is decreased in obese women with polycystic ovarian syndrome. NL = normal (those without PCOS); PCOS = polycystic ovarian syndrome. (From Dunaif, 1989, with permission.) Citation: CHAPTER 18 Polycystic Ovarian Syndrome and Hyperandrogenism, Hoffman BL, Schorge JO, Halvorson LM, Hamid CA, Corton MM, Schaffer JI. Williams Gynecology, 4e; 2020. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2658&sectionid=241010058 Accessed: January 08, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved Acanthosis nigricans A thick grey-brown velvety plaque in flexure areas such as back of neck, axillae, waist, grown, infra-mammary crease (below the breast). A cutaneous marker of insulin resistance D Insulin resistance leads to hyperinsulinemia → keratinocyte growth - In one study of women with PCOS, acanthosis nigricans was found in 70% of participants with metabolic syndrome and 45% without metabolic syndrome. In another study of women with PCOS, the rate of acanthosis was 2x that in obese individuals than those with a normal BMI. Acanthosis nigricans and multiple small pedunculated acrochordons (skin tags) in the neck crease. Both are dermatologic signs of insulin resistance. Citation: CHAPTER 18 Polycystic Ovarian Syndrome and Hyperandrogenism, Hoffman BL, Schorge JO, Halvorson LM, Hamid CA, Corton MM, Schaffer JI. Williams Gynecology, 4e; 2020. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2658&sectionid=241010058 Accessed: January 08, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved Impaired glucose tolerance and T2DM Impaired blood glucose control is a continuum Insulin resistance → impaired glucose tolerance/ prediabetes → T2DM Impaired glucose tolerance: fasting glucose of 6.1-6.9 mmol/L or Hb A1c of 6.0-6.4% or 2 hour post oral glucose tolerance test with 75 grams of glucose 7.8-11 mmol/L. Impaired glucose tolerance and T2DM People with PCOS are at increased risk of developing IGT and T2DM In obese ppl with PCOS prevalence of IGT is 30% and T2DM is 7% Even after adjusting for BMI, people with PCOS remain more likely to have T2DM Those who are anovulatory tend to have a higher degree of IR than those who ovulate Impaired glucose tolerance and T2DM 75 grams oral glucose tolerance test should be used to screen for IGT and T2DM. This constitutes a fasting and 2-hour post glucose load fasting blood glucose test. If this is too inconvenient, patients can be screened with fasting blood glucose or HbA1c test, but these are less sensitive. Some guidelines only recommend OGTT in high-risk women BMI > 25 kg/m2 or BMI > 23 kg/m2 in Asian women, history of abnormal glucose tolerance or family history of diabetes, hypertension, or high risk ethnicity and those planning pregnancy or seeking fertility treatment. In all other cases, A1c is sufficient.  Endometrial Neoplasia 3-4 fold increased risk of endometrial neoplasia/cancer in * people with PCOS Endometrial hyperplasia and risk of mitogenic changes increase with anovulation and unopposed estrogen The effects of hyperandrogenism, hyperinsulinemia and obesity - decrease circulating SHBG and increase circulating estrogen - Few women develop endometrial cancer below the age of 40 Most of these women are obese and have and have chronic anovulation or both Metabolic Syndrome (METS) Metabolic syndrome is characterized by insulin resistance, obesity, dyslipidemia, and hypertension. Increased androgens alone (independent of body weight and IR) has been shown to be a risk factor for METS. METS is associated with a greater risk of cardiovascular disease and and T2DM Prevalence is approx. 45% in women with PCOS compared to age-matched controls A. Women with polycystic ovarian syndrome (PCOS) have an increased risk of metabolic syndrome compared with age-adjusted controls and with women from the Third National Health and Nutrition Survey (NHANES III). B. In women with PCOS, the risk of metabolic syndrome begins earlier than in controls or those from NHANES III. NHANES III collected data from a representative sample of the noninstitutionalized civilian U.S. population from 1988 through 1994. (From Dokras, 2005, with permission.) Citation: CHAPTER 18 Polycystic Ovarian Syndrome and Hyperandrogenism, Hoffman BL, Schorge JO, Halvorson LM, Hamid CA, Corton MM, Schaffer JI. Williams Gynecology, 4e; 2020. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=2658&sectionid=241010058 Accessed: January 08, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved Cardiovascular disease (CVD) METS is an independent risk factor for CVD One small study showed a 7.4 relative risk of myocardial infarction in participants with PCOS compared to controls Women with PCOS should have cardiovascular risk factors identified and treated Complications in Pregnancy Increased rate of early miscarriage (30-50%) compared to a baseline rate of 15% Etiology is unclear Overweight, Obesity and insulin resistance are all risk factors for miscarriage Increased risk of hypertensive disorders, gestational diabetes (GDM), and preterm birth GDM risk exists in PCOS, independent of weight, but risk increases with increasing BMI Complications in Pregnancy Due to an increase in the use of fertility interventions, multi-fetal gestations risk increases → increases risk of maternal and neonatal complications Psychological complications Increased risk of anxiety and depression, eating disorders and negative body image References Bartelme KM. Polycystic Ovary Syndrome. In: O'Connell M, Smith JA. eds. Women's Health Across the Lifespan, 2e. McGraw Hill; 2019. Accessed December 27, 2023. https://accessmedicine-mhmedical- com.ccnm.idm.oclc.org/content.aspx?bookid=2575&sectionid=213570437 Polycystic Ovarian Syndrome and Hyperandrogenism. In: Hoffman BL, Schorge JO, Halvorson LM, Hamid CA, Corton MM, Schaffer JI. eds. Williams Gynecology, 4e. McGraw Hill; 2020. Accessed January 6th 2024. https://accessmedicine-mhmedical- com.ccnm.idm.oclc.org/content.aspx?bookid=2658&sectionid=241010058