Polycystic Ovary Syndrome and Hyperandrogenism Lisa G. Soldat, MD, MS, FAAFP ACTIVITY DISCLAIMER The material presented here is being made available by the American Academy of Family Physicians for educational purposes only. This material is not intended to represent the only, nor necessarily best, methods or procedures appropriate for the medical situations discussed. Rather, it is intended to present an approach, view, statement, or opinion of the faculty, which may be helpful to others who face similar situations. The AAFP disclaims any and all liability for injury or other damages resulting to any individual using this material and for all claims that might arise out of the use of the techniques demonstrated therein by such individuals, whether these claims shall be asserted by a physician or any other person. Every effort has been made to ensure the accuracy of the data presented here. Physicians may care to check specific details such as drug doses and contraindications, etc., in standard sources prior to clinical application. This material might contain recommendations/guidelines developed by other organizations. Please note that although these guidelines might be included, this does not necessarily imply the endorsement by the AAFP. DISCLOSURE It is the policy of the AAFP that all individuals in a position to control content disclose any relationships with commercial interests upon nomination/invitation of participation. Disclosure documents are reviewed for potential conflict of interest (COI), and if identified, conflicts are resolved prior to confirmation of participation. Only those participants who had no conflict of interest or who agreed to an identified resolution process prior to their participation were involved in this CME activity. All individuals in a position to control content for this activity have indicated they have no relevant financial relationships to disclose. The content of my material/presentation in this CME activity will include discussion of unapproved or investigational uses of products or devices as indicated: Combination oral contraceptives off label for use of hirsutism and hyperandnogenism. Lisa G. Soldat, MD, MS, FAAFP Faculty Physician, Family Health Center, Broadlawns Medical Center; Adjunct Clinical Assistant Professor in Family Medicine, University of Iowa Carver College of Medicine; Adjunct Assistant Professor of Family Medicine, Des Moines University College of Osteopathic Medicine. Dr. Soldat is a faculty physician at Broadlawns Medical Center, the county hospital serving the Polk County (greater Des Moines, IA, area) population, with an emphasis on meeting the needs of the underserved members of the community. She has been teaching since 2003 and focuses on women's health and obstetric ultrasound, as well as wilderness medicine and international medicine. Dr. Soldat believes that family medicine s most critical challenge is training doctors with a broad skill set to meet the needs of patients in any community, including retaining obstetric skills, particularly for physicians who choose to practice in rural settings worldwide. Since 2012, she has teamed up with other Iowa family physicians to provide assistance in the development of family medicine as a specialty in Indonesia. Dr. Soldat is an AAFP Fellow. Learning Objectives 1. Recognize clinical signs and symptoms of PCOS and perform an evidence-based workup to confirm diagnosis. Audience Engagement System Step 1 Step 2 Step 3 2. Develop a treatment plan that targets specific manifestations and individualized patient goals. 3. Develop a treatment regimen that takes into account comorbidities, as well as the patient s desire for pregnancy. 4. Counsel patients on lifestyle. modifications that should be used in addition to medical treatments for optimal results. 1
Epidemiology One of the most common endocrinopathies in women In reproductive age women: 6-7% prevalence In obese/overweight women: 28% prevalence Lifelong Implications Increased risk for Metabolic syndrome Type 2 diabetes Cardiovascular disease Endometrial hyperplasia What is PCOS? Abnormal function of the hypothalamic-pituitary-ovarian (HPO) axis due to ovarian dysfunction Abnormal androgen and estrogen metabolism Ovarian dysfunction leads to abnormal control of gonadotropin production Elevated serum levels of androgenic hormones Testosterone, androstenedione, DHEA-S High individual variability, including normal levels Complex Etiology Multiple genetic variants regulating Gonadotropin secretion and action (LH/FSH) Insulin secretion and action (insulin resistance) Weight and energy regulation (obesity) Androgen biosynthesis and action (excess androgens) Environmental factors Diet and associated obesity In utero programming? Intrauterine environment Congenital androgenization Disturbed fetal nutrition Hyperpuberty : Prenatal programming for LH excess at puberty Postnatal contributors may be influenced by prenatal events Obesity: the most common postnatal environmental contributor Pathophysiology Androgen excess Ovarian > adrenal androgen secretion Testosterone, androstenedione, DHEA-S peripheral insulin resistance and hyperinsulinemia Independent of effect of obesity Increases androgen response to LH Suppresses SHBG level 2
Follicular Develoment Follicles ripen prematurely Commit to atresia before oocytes can be sustained Failure to rupture leads to theca cell stimulation and multiple cysts Theca cells Source of androgen production Gene for DENNDIA.V2 protein involved in high levels of androgen production as seen in PCOS Overexpression of LH receptor in theca and granulosa cells Increased serum LH Theca cell stimulation Increased androgen production Decreased FSH Failure of granulosa cells to aromatize androgens into estrogen Decreased estrogen production Ovarian Hyperandrogenism Anovulation Increased production of ovarian and adrenal androgens LH excess A Simplistic View Hyperinsulinemia Android fat distribution Ovarian Hyperandrogenism Hyperinsulinemia Insulin Resistance Increased peripheral insulin resistance (muscle) Menstrual dysfunction Hirsutism Polycystic ovaries Obesity Learning Objective #1 Recognize clinical signs and symptoms of PCOS and perform an evidence-based workup to confirm diagnosis. A Case of Oligomenorrhea 30 y.o., healthy, no meds CC: irregular menstrual cycles Menarche age 12, somewhat irregular over the years For the past year, menses q 4-5 months LMP 6 months ago What other symptoms would make you suspect PCOS? 3
Presenting symptoms in adults A. Obesity B. Hypertension C. Acanthosis nigricans D. Infertility E. A, C and D Infertility (74%) Menstrual dysfunction (amenorrhea/aub) (70%) Hyperandrogenism (hirsutism/acne) (69%) Obesity (40-85%) No symptoms (20%) Differential Diagnosis Onset and Progression Hyperandrogenism Nonclassical congenital adrenal hyperplasia Androgen-secreting tumors Cushing syndrome Acromegaly Exogenous androgens Menstrual dysfunction Pregnancy Extreme exertion Eating disorders Rapid weight changes Premature ovarian failure Thyroid disorders (hypo- and hyper) Genetic defects of insulin metabolism Primary hypothalamic amenorrhea Hyperprolactinemia (pituitary adenoma) Medications Symptoms usually begin in perimenarchal years May initially have normal cycles Followed by cycle irregularity and weight gain Slow progression Sudden onset or rapid progression (<6 months) suggest other diagnoses such as Cushing s syndrome, ovarian or adrenal tumors Case: 15 year old girl Multiple Classification Systems Menarche one year ago Irregular menses, every 1-3 months Other symptoms: obesity and hirsutism Mom worries she has PCOS NIH Consensus Criteria (1990) (All required) Oligo or anovulatory menstrual dysfunction Clinical and/or biochemical signs of Rotterdam criteria (2003) (2 of 3 required) Oligo or anovulation Clinical and/or biochemical signs of AES definition (2008) (All required) Oligo or anovulation and/or polycystic ovaries on ultrasound Clinical and/or biochemical signs of Does she need a pelvic ultrasound to confirm PCOS? A. True B. False Exclusion of other disorders: NCCAH, androgen secreting tumors Polycystic ovaries by ultrasound Exclusion of other androgen excess or ovulatory disorders 4
2012: NIH Evidence-Based Methodology Workshop on PCOS: endorses Rotterdam because it is the most inclusive Q: Should any of these women be screened for PCOS? NIH Consensus Criteria (1990) (All required) Oligo or anovulatory menstrual dysfunction Clinical and/or biochemical signs of Exclusion of other disorders: NCCAH, androgen secreting tumors Rotterdam criteria (2003) (2 of 3 required) Oligo or anovulation Clinical and/or biochemical signs of Polycystic ovaries by ultrasound AES definition (2008) (All required) Oligo or anovulation and/or polycystic ovaries on ultrasound Clinical and/or biochemical signs of Exclusion of other androgen excess or ovulatory disorders Polycystic ovaries on ultrasound not needed to diagnose PCOS if the other 2 criteria are met A. 16 y.o. with delayed adrenarche B. 18 y.o. with increasing obesity and oligomenorrhea since menarche C. 30 y.o. with an aunt with PCOS D. Asymptomatic 25 y.o. with incidental finding of polycystic ovaries on ultrasound E. None should be screened PCOS more common in certain groups Clinical Features Oligoovulatory infertility Obesity and/or insulin resistance Type 1, type 2 or gestational diabetes History of premature adrenarche First degree relative with PCOS Women using valproate Common Menstrual dysfunction Hyperandrogenism Polycystic ovaries Other Metabolic issues/cardiovascular risks + Obesity Mood disorders Depression/anxiety Impaired quality of life Eating disorders (eg binge eating) Menstrual Dysfunction Typically begins in perimenarchal period Menarche may be delayed Pattern is typically oligomenorrhea (< 9 periods/year) Amenorrhea also possible Periods may become more regular > 40 years old Hyperandrogenism Clinical signs Terminal hair growth 70% pts manifest in androgen-dependent body areas Acne Androgenetic alopecia Acanthosis nigricans Neck, axillae, under breasts, vulva Skin tags 5
Polycystic Ovaries Transvaginal ultrasound most accurate Non-specific finding Seen in 1/3 of young women without PCOS If no clinical symptoms, no further workup Rotterdam Ultrasound Criteria (Adults) > 12 follicles in each ovary measuring 2-9 mm² and/or Increased ovarian volume (>10 ml) of at least 1 ovary 0.5 x length x width x thickness https://commons.wikimedia.org/wiki/file:polycystic_ovary.jpg Polycystic ovarian morphology does not predict future development of PCOS Initial Evaluation >50% of normal cycling adult women have >12 follicles per ovary Follicle number and ovarian size decrease with age regardless of PCOS No well-established age-based ultrasound criteria for women > 40 years History Menstrual dysfunction Correlated to patient age Medication use Mask symptoms Oral contraceptives Topical or systemic acne medications Mimic symptoms Androgenic steroids Antiepileptic drugs Speed of symptom progression Physical exam Clinical features suggestive of Hirsutism Treatment-resistant acne Acanthosis nigricans Male-pattern hair loss Obesity BMI Waist circumference Case 35 y.o. G2 P2 CC: LMP 3 months ago Periods usually every 45-60 days since age 18 History of gestational diabetes Physical exam: BMI 23, thinning scalp hair Which test(s) is/are not necessary as part of the initial evaluation? A. Fasting insulin level B. LH/FSH ratio C. Pregnancy test D. Total testosterone level E. A & B 6
Choice of Testing Based on Symptoms Testosterone Menstrual dysfunction Pregnancy test Prolactin (hyperprolactinemia) TSH (thyroid dysfunction) FSH (ovarian insufficiency) LH usually NOT necessary Conflicting evidence on diagnostic usefulness of LH alone or LH/FSH ratio Use to rule out other causes of oligomenorrhea Hyperandrogenic symptoms Testosterone DHEA-S? Other endocrine screening tests if indicated PCOS: low-normal sex hormone binding globulin (SHBG) and high-normal total testosterone Elevated testosterone is one of the most consistent biochemical features Either total or free serum testosterone levels can be used Depends on reliability and cost-effectiveness of available assays Begin with total testosterone if assay is reliable Free testosterone if equilibrium dialysis method is used Pitfalls of Testosterone Assays Automated assays are not reliable for measuring lower testosterone levels found in females Normal range is likely abnormally broad May include women with unrecognized androgen excess May need to repeat testing in a reference laboratory with more validated assays and controls Interpreting Testosterone Levels Serum total testosterone 40 60 ng/dl Upper limit of normal 29 150 ng/dl Typical for PCOS > 150 200 ng/dl Suggests virilizing neoplasm May be diagnostically useful if very high or very low Optimal cutoffs can be found, but no single cutoff has sufficiently high sensitivity and specificity Testosterone Level is Elevated, now what? If elevated, may consider: Endocrine screening panel To exclude other endocrine disorders Pelvis and adrenal ultrasound To exclude other pathology Common PCOS Mimics Abnormality Possible diagnosis Differs from PCOS Elevated 17 Nonclassic congenital hydroxyprogesterone adrenal hyperplasia Similar to PCOS, more common in certain ethnic groups Elevated DHEA S Adrenal tumor Rapid onset/progression Elevated cortisol Cushing syndrome or Cortisol resistance Hypertension, supraclavicular fat pads, purple abdominal striae, or proximal muscle weakness Abnormal prolactin Hyperprolactinemia May be elevated up to 40 mg/dl in PCOS Abnormal TSH Thyroid disorder Symptoms of thyroid dysfunction Abnormal IGF 1 Acromegaly Enlarged jaw, hands, feet 7
mid point of lecture Hyperandrogenism Menstrual dysfunction Endocrine screening tests negative for other disorders 99% specificity for PCOS Learning Objective #2 Develop a treatment plan that targets specific manifestations and individualized patient goals Treatment Goals 1. Prevent endometrial hyperplasia/cancer 2. Manage menstrual dysfunction symptoms 3. Address hyperandrogenic symptoms Case 28 y.o. nulligravida Chief complaint: desires pregnancy Presentation: Irregular menses, approximately twice a year Obese Family history of cardiovascular disease Has tried to conceive for the last 2 years Which of these is not part of the initial treatment plan? A. Address potential for endometrial hyperplasia B. Begin formal infertility workup now C. Screen for diabetes D. Lifestyle modification including weight loss 8
Treatment Options Lifestyle modification Weight loss, exercise, diet Pharmacologic options Hormonal Nonhormonal Weight Reduction First line intervention for most problems Restores ovulatory cycles Decreases serum testosterone levels Improves metabolic risk Improves fertility Choice depends on individual s needs and goals Hormonal Options Choice based on 1. Need for endometrial protection 2. Symptoms Heavy menses Anovulation Hirsutism (off-label use in US) Acne 3. Contraception needs Combined Hormonal Contraceptives First line for Menstrual dysfunction Acne Hirsutism Estrogen reduces circulating free androgens Progestins decrease ovarian androgen production Endometrial Protection Progestin antagonizes estrogen s effect of endometrial proliferation Hormonal options Combined OCPs Extended cycle OCPs may provide more consistent effect than monthly OCPs Progestin only Intermittent Continuous Recommended: Withdrawal bleeding every 3-4 months Menstrual Dysfunction First line: hormonal contraceptives Oral Patch Vaginal ring Second-line: metformin Better as adjunct to hormones 9
Treatment for Hyperandrogenism First line: hormonal contraceptives (pills, patch, ring) off-label use in US Nonhormonal treatment May be required after 6 months of hormonal therapy OR if hormonal use contraindicated 2013 Endocrine Society Clinical Practice Guidelines on the Diagnosis and Treatment of Polycystic Ovary Syndrome Risks of OC Use PCOS does not change level of risk for metabolic adverse effects and cardiovascular complications PCOS is not an independent risk factor for VTE Risk factors for VTE common in PCOS OCPs Obesity (BMI > 30 kg/m2) Age (> 40 years) Family history of VTE Caution using OCs if BMI > 30 and age > 40 Estrogen Component Adolescents: 30-35 mcg ethinyl estradiol < 20 mcg may be less effective in controlling menstrual irregularity especially in obese adolescents Adults: 20 mcg ethinyl estradiol 30 35 mcg may be needed if inadequate symptom control 50 mcg may be indicated if heavy bleeding or obese Switch to lower estrogen dose option once symptoms controlled Progestin Component All types will treat hyperandrogenic symptoms Primarily treated by estrogen component Best option: anti-androgenic or low androgenic properties Drospirinone (anti-androgen) Norgestimate (low androgenicity) Ethynodiol diacetate (low androgenicity) Lowest VTE risk (but more androgenic) Norethindrone Intermittent Endometrial protection + anovulatory bleeding Not for contraception Progestin-only Options for Endometrial Protection Medroxyprogesterone acetate 5-10 mg for 10-14 days every 1-2 months Natural micronized progesterone 200 mg for 10-14 days every 1-2 months Continuous Endometrial protection + contraception Norethindrone 0.35 mg daily Levonorgestrel-releasing IUD OCPs in Adolescents Best option for all PCOS symptoms Benefits of treatment may outweigh risk of DVT Avoid in girls who haven t completed linear growth Estrogens may inhibit growth May impede weight loss 10
OCPs in Adolescents Continue until sexual maturity reached (5 years after menarche), OR Adequate weight loss achieved Consider trial off OCPs after several years To allow recovery of pituitary-gonadal function To see if menstrual abnormality is still present Other Androgen-Reducing Therapies Gonadotropin releasing hormone (GnRH) agonists If OCs contraindicated or not tolerated Leuprolide acetate (Depot) Add-back estrogen/progestin therapy to avoid bone loss and estrogen deficiency symptoms Metformin Second-line treatment for menstrual dysfunction, obesity and hirsutism Increases peripheral sensitivity to insulin Restores ovulatory menses in 30-50% of PCOS Endometrial protection unclear Use for women with diabetes or gestational diabetes May delay progression of prediabetes Treatment Options: Hirsutism Type Options Comments Mechanical Shaving Electrolysis Laser epilation May improve quality of life, mood disorders Combination OCPs Choose low androgenic progestin Estrogen: 30 35 mcg may be op mal (but risk VTE) (Off label in the US) component Progestin only Efficacy depends on route Oral: variable reduction in sx Depo: high/sustained better Androgen receptor blockers Ornithine decarboxylase inhibitor (Vaniqa ) Spironolactone 25 100 mg BID Flutamide 250 mg daily Finasteride 1 mg daily Adjunct to OCPs or if OCPs contraindicated; Caution: can cause abnormal external genitalia development in males fetuses 13.9 % cream BID $$$$, slow and may worsen acne; Must use indefinitely Learning Objective #3 Develop a treatment regimen that takes into account comorbidities, as well as the patient s desire for pregnancy Cancer Risks? risk for endometrial hyperplasia, but NOT ovarian cancer Possible slight risk of endometrial cancer Already minimal in women < 40 y.o. Routine ultrasound screening for hyperplasia or cancer not recommended in PCOS patients 11
Metabolic Issues 60 80% are obese 70% have dyslipidemia 40% have insulin resistance Independent of body weight 2-5X increase of T2DM compared to general population Cardiometabolic Risk Screening BP and BMI Fasting lipid profile 2-hour oral glucose tolerance test Begin screening by age 30 yo regardless of BMI 75 gram OGTT More sensitive than fasting blood glucose or HgbA1c FBG/HgbA1c may not reliably identify abnormal glucose tolerance found in PCOS If initial OGTT is normal Screen every 2 years, sooner if risk factors Screen annually if impaired glucose tolerance Consensus opinion ACOG, American College of Clinical Endocrinologists, and Androgen Excess Society Test for Insulin Resistance? No validated tests in the clinical setting Consider fasting insulin levels in younger women with either Severe stigmata of insulin resistance or Undergoing ovulation induction Screen for Other Comorbidities Mood disorders PHQ-9 for depression GAD-7 for anxiety Sleep apnea An important determinant of insulin resistance, glucose intolerance and T2DM CPAP may improve insulin sensitivity and diastolic BP Preventative and treatment strategies are the same for patients with or without PCOS First line: Weight loss, diet and exercise Second line: specific treatments based on comorbidity 12
Insulin resistance/type 2 DM Medications may reduce insulin resistance, ovarian androgen production, serum free testosterone concentrations restore ovulatory function Options: Metformin Not recommended: Thiazolidinediones Limited data, potential weight gain, may not be advisable in women without diabetes Unfavorable risk: benefit ratio Case 58 year old woman LMP 3 years ago History of obesity, hirsutism, and oligomenorrhea Will a presumptive/retrospective diagnosis of PCOS be of value? A. Yes B. No Post-Menopausal Women There is no consistent PCOS phenotype Rapid onset of PCOS symptoms after menopause suggests ovarian/adrenal tumors Treatment after menopause is aimed at detecting and managing comorbidities Screening of Family Members Increased risk of PCOS and metabolic issues in first degree relatives Screen for metabolic syndrome and diabetes in family members of both sexes Especially in obese relatives Screen for PCOS in premenopausal female relatives Case 30 y.o. woman with PCOS On OCPs for many years with good resolution of symptoms (oligomenorrhea and hirsutism) She wants to get pregnant She doesn t want to redevelop hirsutism She is not obese, and exercises regularly Discontinue OCPs and. A. Wait and see if she conceives in the next year B. Start metformin C. Start metformin + spironolactone Besides stopping OCPs (obvious), what do you advise? 13
Infertility Weight loss and lifestyle modification may be as effective as medication Attempt prior to ovulation induction Routine fertility workup of both partners Infertility Medications Clomiphene is first-line for BMI < 30 80% ovulation rate; 50% conception rate Consider adding metformin as adjunct Letrozole Ovulation induction is an off label use Better than clomiphene for BMI > 30 Metformin Not recommended unless glucose intolerance present Compared to clomiphene citrate alone: Metformin + clomiphene citrate may ovulation/pregnancy rates but not live births Less Often Recommended Laparoscopic ovarian laser electrocautery Goal is to restore ovulation Pharmacologic strategies usually more effective In vitro fertilization If all else fails risk for multiple gestation and OHSS Learning Objective #4 Counsel patients on lifestyle modifications that should be used in addition to medical treatments for optimal results Lifestyle Modification: what works? Weight loss is first line for obesity Results in serum androgens, insulin and LH levels Lowers glucose and lipid levels 5-10% weight loss may restore ovulatory cycles and metabolic effects No randomized trials or long-term data Which diet works in PCOS? Calorie restriction? Low carbs? High protein? 12 week study of low carb/high protein diet versus high carb/low protein were equally effective Bariatric surgery remains an option 14
Practice Recommendations Contact 1. Rotterdam criteria are the most inclusive and currently favored algorithm for diagnosis 2. Weight loss, diet, and exercise are first-line for most aspects of PCOS 3. Hormonal management using OCs is the pharmacological first line for most symptoms of PCOS Lisa Soldat, MD, MS, FAAFP lsoldat@broadlawns.org 4. Recognize and treat endometrial hyperplasia to prevent risk of cancer 15