Clinical Problems in the Diagnosis and Treatment of PCOS During Adolescence

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Malcolm Davidson
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1 Clinical Problems in the Diagnosis and Treatment of PCOS During Adolescence R a c h a n a S h a h, M D M S T A s s i s t a n t P r o f e s s o r o f P e d i a t r i c s D i v i s i o n o f E n d o c r i n o l o g y a n d D i a b e t e s

2 Disclosures Off-label use of metformin in treatment of PCOS

3 OBJECTIVES Understand clinical presentation of PCOS in teens Describe the diagnostic work-up of PCOS in teenagers Understand short and long-term consequences of PCOS in teens Discuss treatment options for PCOS in teenagers

4 Case: 15 year old Menarche at 12. periods initially regular but this year has only had 4 periods Acne on face, using topical treatments; worse this year Some hair on upper lip, lower back, began at menarche Feeling anxious about school, hanging out less with friends No family history of similar Has gained 10 lbs past year, stopped playing basketball, snacking more BMI 85 th percentile. Exam normal except: flat affect, acne & mild hirsutism face, lower back

5 Questions Is this normal? Should it be evaluated? How? How can we counsel her, regardless of diagnosis?

6 PCOS in Adolescents Under diagnosed in teens, especially lean Symptoms may mimic normal puberty Weight gain Insulin resistance Irregular periods Acne Disease is often EVOLVING and girl may not meet diagnostic criteria YET or may have features of PCOS that resolve with time

7 Diagnostic Challenges Laboratory references for ADULT women Must rule out other conditions (adrenal disorders, tumors) May never have period Ultrasound findings not usually helpful PCOS-like ovaries seen in other diseases Criteria based on transvaginal ultrasounds Ovarian size/shape/cysts are different in teens Larger ovaries with more cysts may be NORMAL Need to establish age-based criteria

8 Diagnostic Challenges Symptoms of PCOS are evolving and may not be readily apparent in adolescents Because the diagnosis has significant lifelong implications including testing, treatments, and related anxiety, diagnosis is made with caution When diagnosis unclear, recommend: Education Treatment of specific symptoms if needed Follow up

9 Dermatologic Issues Hirsutism terminal hair in MALE pattern Does NOT correlate with androgen levels but with IR Found in 69% of PCOS teens Racial/ethnic differences important Acne more severe (cystic, not responding to topical treatments), different pattern (JAWLINE, back, chest), worse with periods Less specific, as 2/3 of normal teens have acne Androgenic alopecia: Scalp hair thinning in male pattern Much less common, incidence not reported Skin issues cause embarrassment, poor self-esteem

10 Hirsutism Scoring (modified Ferriman Gallwey)

11 Modified Ferriman Gallwey Rate 0-4 on 9 body areas >6-8=hirsutism in Caucasian and African American Suggested cut-off of 4 in East Asian Proposed higher cut-off in Middle Eastern/Southeast Indian and other populations Mostly helpful as a baseline and to follow effect of treatment

12 Anovulatory Cycles Can have regular periods (10-15%), increased frequency, heavy bleeding Oligomenorrhea (infrequent periods): >35 day cycles (45 in teens) or <9/year (8 in teens) Amenorrhea primary or secondary (>90 day interval) Risk of endometrial hyperplasia & uterine cancer Degree of menstrual dysfunction correlates with IR

13 The Menstrual Cycle as a Vital Sign POPULATION NORMS IN THE US Menarche (median age): years Mean cycle interval: 32.2 days in first gynecologic year Menstrual cycle interval: typically days Menstrual flow length: 7 days Menstrual product use: 3 6 pads/tampons per day ASK at well child visits and offer anticipatory guidance EVALUATE if the girl s cycles are outside these norms

14 PCOS is a Cardiometabolic Risk Factor EVEN IF NOT OBESE more likely to have: Endothelial dysfunction, increased carotid IMT & CAC Markers of chronic systemic inflammation Diseases with cardiometabolic risks Metabolic Syndrome (35% in adolescent cohorts!) Type 2 diabetes, insulin resistance Hyperlipidemia Hypertension Sleep apnea Fatty liver

15 Psychiatric Risk in PCOS Increased depression and anxiety Adult study: 35% met criteria for depression (vs 7% control population) 45% with anxiety (vs 18% control) Depression associated with BMI and insulin resistance Disordered eating (binge-eating, bulimia) more common Poor body image due to: weight, hirsutism, acne, and fertility concerns SCREEN AND REFER!! Hormonal treatment and even nutrition advice can exacerbate

16 Differential Diagnosis Normal puberty Idiopathic hirsutism (15-30%) Non-classical congenital adrenal hyperplasia (3%) Androgen-secreting adrenal/ovarian tumor Exogenous androgen exposure Cushing s syndrome Hypothyroidism Prolactinoma Other DSD: androgen-insensitivity, gonadal dysgenesis, 17-beta HSD deficiency

17 Risk Factors for PCOS Premature adrenarche Low birth weight (SGA, IUGR) Prenatal androgen exposure Genetics (Explain a very small % of heritability) gonadotropin receptor: LHCGR and FSHR, cytoplasmic function glucose homeostasis: PPARgamma, IRS-1 androgen signaling: AR

18 Diagnostic Criteria NIH, 1990 Rotterdam, 2003 (endorsed by Endo society, 2013) 2 of 3 Hyperandrogenism x x x Oligoovulation x x x or PCOM x x AE-PCOS, 2006 Hyperandrogenism + one other other entities are excluded that would cause excess androgen activity

19 Diagnosis in Adolescence Witchel, et al Hyperandrogenism moderate/severe hirsutism=hyperandrogenism Moderate/severe acne NOT responding to topical should be worked up Persistent elevation of total or free testosterone (cut off assay specific) Oligoovulation <21 days or >45 days (once 2 years post-menarche) >90 days any time Amenorrhea by age 15 or 3 years post thelarche No good data to define PCOM in adolescents, do not use US for dx

20 Laboratory Tests Diagnostic for PCOS: Increased bioactive T Testosterone profile total testosterone: HIGH or normal sex hormone binding globulin: LOW free testosterone: HIGH DHEAS elevated in about 35%, but only 5% with only DHEAS and no T elevation Measure T by LC/MS/MS in AM

21 Laboratory Tests, cont. Rule out other causes Pregnancy Thyroid prolactin 17-hydroxyprogesterone(CAH) LH, FSH Bleeding disorders (if heavy/frequent) Other, as indicated (cortisol, other adrenal androgens) Comorbidities Glucose, hemoglobin A1c, insulin (consider OGTT) Fasting lipid profile Liver enzymes

22 When to Ultrasound? Signs/symptoms of androgen-secreting tumor Marked testosterone elevation (>200) Rapid onset of virilization cliteromegaly/voice deepening Evaluate anatomy Primary amenorrhea Pain or palpable mass in pelvis

23 Adult Criteria for PCOS morphology on ultrasound (transvaginal) Increased ovarian volume >10 cm 3 for one or both ovaries -or- Multiple cysts Counting both ovaries, at least cysts between 2 and 9 mm (changed to reflect more sensitive methods!) No cysts >10 mm Cysts are common in teens and ovarian size is largest at menarche. Norms in adolescents have NOT been established

24 Other Causes of PCOSlike Ovaries Normal women with normal ovulatory function (16%) Hyperprolactinaemia (50%) Hypothyroidism (36.4%) Hypogonadotrophic hypogonadism (23.7%) CAH (100%) Androgen-producing adrenal tumours Prevalence in PCOS (~ 53%) Abdel Gadir et al 92

25 Insulin Resistance in PCOS Increased insulin levels and decreased sensitivity amplify the hormonal features of PCOS. Treatment of insulin resistance may improve hyperandrogenism and even restore ovulation. May be tissue-specific, such that muscle/liver is resistant and ovary/adrenals are sensitive. Or pathway specific, with metabolic pathways resistant, and steroidogenic or mitogenic pathways sensitive Even in non-pcos women, IR can cause increased T but ovaries of PCOS women may be more sensitive

26 Insulin Effects in PCOS Stimulate ovarian theca cell androgenic pathways Augment LH-stimulated androgen secretion by induction of steroidogenic enzymes Lower hepatic SHBG production Alter hypothalamic LH regulation by GnRH Increase amplitude & frequency of LH pulses Enhance AMH to cause mid-antral follicular arrest Upregulate adrenal steroidogenic enzymes and sensitivity to ACTH

27 Jayasena CN et al. Nature Rev. Endo. 2014

28 Goals of PCOS Treatment Reduce production and effects of androgens Protect endometrium from prolonged estrogen Reduce weight and cardiometabolic risk with lifestyle changes Improve insulin sensitivity Restore fertility by inducing ovulatory cycles Treatment tailored to specific symptoms

29 Hormonal Treatment Oral contraceptives; mcg of ethinyl estradiol Some progestins less androgenic (cyproterone acetate*, drospirenone, desogestrel) but higher clot risk NIH guidelines: no specific recommendations, use any combined estrogen/progesterone contraceptive Contraindications: clot risk, migraine with aura, very high risk of breast/gyn cancer (BRCA positive, personal history) Medroxyprogesterone or progesterone for 7-10 days of each cycle (or every 3-4 months if no spontaneous menses) *not FDA-approved, due to concerns of hepatotoxicity

30 Effective even without IR Metformin Biguanide insulin sensitizer, inhibits hepatic GNG and increases peripheral glucose uptake Results INDEPENDENT of weight loss. Side effects: GI (common): nausea, diarrhea, gas (resolve with time) Vitamin B12 deficiency Lactic acidosis (negligible in non-dm) Titrate: start 500 mg/day and increase to max 2500 mg/day

31 Dermatologic Acne: topical treatments, antibiotics, retinoids Hirsutism: topical eflornithine (Vaniqa), slows growth Laser, electrolysis, waxing, shaving, depilatories, etc.. Even with androgen control, can only slow growth & prevent new growth already present follicles will not regress If considering permanent option, control androgens FIRST Alopecia: Minoxidil (Rogaine) to affected areas

32 Anti-androgens Spironolactone (competitive inhibitor of androgen receptor and inhibits 5a reductase); reduction in hirsutism and acne Monitor: K, BP Teratogenic! finasteride (5a reductase inhibitor) only blocks type 2 enzyme, and type 1 & 2 activated in PCOS; less effective for hirsutism Flutamide (non-steroidal anti-androgen) restore ovulation, reduce androgen. Risk of fatal hepatitis, anemia

33 Treatment Challenges in Teens Oral contraceptives: growth suppression social stigma (parents/child) side effects (mood, weight, headaches) compliance Metformin: side effects often not tolerated Effect takes time! Compliance even harder, twice a day!

34 Treatment Challenges in Teens Spironolactone: birth defects if pregnancy (feminization of male fetus) dizziness/orthostatic hypotension, high K Lifestyle interventions (diet/exercise): need family support financial barriers social barriers MOTIVATION

35 Is this normal? Back to our case NO, irregular menses >2 years post-menarche warrants evaluation Should it be evaluated? How? Laboratory testing for cause of symptoms (T, 17OHP, thyroid, gonadotropins, prolactin pregnancy test), metabolic screen if PCOS How can we counsel her, regardless of diagnosis? Lifestyle management for weight gain, psychological counseling for mood

36 Summary PCOS is common in teens, yet diagnosis may be challenging Clinical history and basic laboratory evaluation are sufficient for diagnosis in most cases Treatment is aimed at presenting symptoms and prevention of cardiometabolic disease Counseling on lifestyle modification (Nutrition) and regular metabolic screening are standard of care Screening for depression and other psychiatric disorders should also be done routinely

37 CHOP Endocrine PCOS Clinic Multidisciplinary, all pediatric providers Endocrinologist (Dr. Rachana Shah) Dermatologist (Dr. Marissa Perman) Nutritionist (Sarah Barnes, RD) Patients/families meet with multiple providers at one clinic visit to have all their needs met Laser hair removal offered through Dermatology; may be able to get insurance coverage

PCOS IN ADOLESCENTS: EARLY DETECTION AND INTERVENTION

PCOS IN ADOLESCENTS: EARLY DETECTION AND INTERVENTION R A C H A N A S H A H, M D M S T R A S S I S TA N T P R O F E S S O R O F P E D I AT R I C S D I V I S I O N O F E N D O C R I N O L O G Y A N D D