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Polycystic ovarian syndrome and non-classic congenital adrenal hyperplasia: Challenges of diagnosis and management Serwa Gyamfi, MD and Sharyn Malcolm,

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Presentation on theme: "Polycystic ovarian syndrome and non-classic congenital adrenal hyperplasia: Challenges of diagnosis and management Serwa Gyamfi, MD and Sharyn Malcolm,"— Presentation transcript:

1 Polycystic ovarian syndrome and non-classic congenital adrenal hyperplasia: Challenges of diagnosis and management Serwa Gyamfi, MD and Sharyn Malcolm, MD, MPH Children’s National Health System Division of Adolescent and Young Adult Medicine Washington, DC American College Health Association’s Annual Meeting June 1st 2018 1

2 Serwa Gyamfi, MD and Sharyn Malcolm, MD, MPH Have documented no financial relationships to disclose or Conflicts of Interest (COIs) to resolve. 2

3 OBJECTIVES Recognize the clinical presentations of polycystic ovarian syndrome (PCOS) Recognize the clinical presentations of non-classic congenital adrenal hyperplasia (NCAH) Compare the diagnostic criteria for PCOS and NCAH Discuss treatment modalities and their effectiveness for PCOS and NCAH 3

4 PCOS is the most common endocrine disorder of reproductive age females

5 PCOS OBJECTIVES Define the entity of PCOS
List the different diagnostic criteria for PCOS Understand the pathophysiologic theories of PCOS Understand the approach to work-up of a patient with characteristics of PCOS Understand the different treatment modalities in the management of PCOS and potential psychopharmacologic medication interactions 5

6 CASE An 18 y/o freshman presents for her annual visit but is also concerned that she may be depressed. She had menarche at age 14 and she has had menses every 2 months for the past 2 years, however has missed 4 months of her cycle most recently. She has a BMI of 29 and in the past year has experience increased facial hair growth. She has never had acne. She asks: “why do I have some much facial hair?”

7 EPIDEMIOLOGY PCOS occurs in 6-10% of reproductive age women
Most common cause of excess androgen production It is a leading cause of infertility in women It is associated with: Metabolic syndrome (cardiovascular disease, insulin resistance, sleep- disordered breathing and excessive daytime sleepiness, NAFLD) Type 2 diabetes Dysfunctional Uterine bleeding Endometrial cancer Psychosocial (depression, anxiety, cosmetic concerns)

8 DIAGNOSTIC CRITERIA NIH Definition 1990 Rotterdam Definition 2004
Androgen Excess Society Definition 2006 ALL REQUIRED TWO of THREE Hyperandrogenism/ Hyperandrogenemia Hyperandrogenism Ovulatory dysfunction or Ultrasonographic PCOS morphology Ovulatory dysfunction and/or Ultrasonographic Exclude: -non-classic CAH -hyperprolactinemia -androgen secreting tumors

9 OBJECTIVES Understand the pathophysiologic theories of PCOS 9

10 THEORIES OF PATHOPHYSIOLOGY
Abnormal pituitary function Abnormal steroidogenesis Ovaries Adrenals Insulin Resistance Chromosome 2p16.3?

11 ABNORMAL PITUITARY FUNCTION
Gonadotropin releasing hormone (GnRH) Adrenocorticotropic hormone (ACTH) Insulin promotes hyperandrogenism Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) Estrone controls LH release DHEA-S Androstenedione  Testosterone Estrone (Marx T and Mehta A, 2003)

12 FUNCTIONAL OVARIAN HYPERANDROGENISM
(Chang R, 2007)

13 OVARIAN DYSREGULATION OF STEROIDOGENESIS
Excessive growth of small ovarian follicles Polycystic appearance of the ovary Thecal and stromal hyperplasia

14 FUNCTIONAL ADRENAL HYPERANDROGENISM
Zona fasciculata and zona reticularis of the adrenals: Testosterone DHEA Androstenedione In PCOS there is excess production despite normal stimulation of the adrenals

15 ROLE OF INSULIN RESISTANCE
Hyperinsulinemia Stimulates thecal cell secretion of androgens Inhibits hepatic sex-hormone binding globulin (SHBG) production Blocks the normal cellular down-regulation of response to LH Seen in obese and non-obese women with PCOS

16 OBJECTIVES Understand the approach to work-up of a patient with
characteristics of PCOS 16

17 Hyperandrogenism (eg, hirsutism, severe acne, and/or pattern alopecia)
CLINICAL FEATURES Clinical Feature Prevalence Menstrual irregularity (eg, oligo- or amenorrhea, or irregular bleeding) 75% Hyperandrogenism (eg, hirsutism, severe acne, and/or pattern alopecia) 60–80% Polycystic ovaries Obesity 35–80% Family History Hirsutism Adrenal enzyme deficiencies Menstrual disorders including PCOS Diabetes Infertility

18 DIFFERENTIAL DIAGNOSIS
Medications Androgenic drugs (eg, anabolic steroids) Valproic acid Hyperprolactinemia Prolactinoma Ovarian steroidogenic blocks Acromegaly Precocious puberty Premature pubarche Other rare causes Hermaphroditism Portohepatic shunting Pregnancy Adrenal disorders Congenital adrenal hyperplasia Nonclassic 21-hydroxylase deficiency Cushing Syndrome Cortisol resistance Apparent cortisone reductase deficiency Insulin resistance syndrome Virilizing tumors Ovarian or adrenal Thyroid dysfunction Peripheral androgen overproduction Obesity Idiopathic hyperandrogenism

19 PHYSICAL EXAM FINDINGS
Hirsutism Acne Insulin Resistance Obesity Acanthosis nigricans Virilization Increased upper body mass Male pattern baldness Clitoromegaly (rare) Enlarged ovaries  Galactorrhea

20 NORMAL HAIR DISTRIBUTION
Female Male

21 FERRIMAN-GALLWEY SCORING SYSTEM
A score greater than 8 denotes hirsutism ( 2009)

22 PHENOTYPIC VARIATION -This table from the Androgen Excess Society shows the Variability in presentation of PCOS PCOS must first be considered as a disorder of hyperandrogenism There may be forms of PCOS without overt evidence of hyperandrogenism which however is uncommon. If diagnostic criteria differ then physical exam and phenotypic expression differs therefore as pediatricians we should be familiar with the variations in clinical presentation of this syndrome Androgen Excess Society Guidelines, 2006.

23 DIAGNOSTIC EVALUATION
Labs Total testosterone* Free testosterone* DHEA-S* TFTs* Prolactin* 17-OH Progesterone* LH:FSH >2:1 SHBG Androstenedione bHCG* AMH For patients with signs of insulin resistance: OGTT Fasting lipid panel LFTs Insulin level

24 DIAGNOSTIC EVALUATION
Adjunctive imaging studies Pelvic ultrasound ≥12 follicles 2-9 mm ovary volume >10ml Computerized Tomography (CT) abdomen/pelvis

25 DIAGNOSTIC CRITERIA NIH Definition 1990 Rotterdam Definition 2004
Androgen Excess Society Definition 2006 ALL REQUIRED TWO of THREE Hyperandrogenism/ Hyperandrogenemia Hyperandrogenism Ovulatory dysfunction or Ultrasonographic PCOS morphology Ovulatory dysfunction and/or Ultrasonographic Exclude: -non-classic CAH -hyperprolactinemia -androgen secreting tumors

26 The Challenge: Adolescents & Young Adults
Challenges in diagnosing PCOS in adolescents: Difficult to distinguish physiologic anovulation/oligomenorrhea from that of PCOS Diagnosis can only be made 2 yrs after menarche Multifollicular ovaries can be normal Polycystic ovaries may be missed by transabdominal ultrasound Acne and mild hirsutism are common No standardized Ferriman-Gallwey scoring system in adolescents and young adults

27 OBJECTIVES Understand the different treatment modalities in
the management of PCOS and potential psychopharmacologic medication interactions 27

28 TREATMENT Lifestyle changes Medications Cosmetic treatment
(Domecq P et al., 2013) Medications Cosmetic treatment

29 TREATMENT Menstrual irregularities Hyperandrogenism Hyperinsulinemia
Oral contraceptives Other contraceptive methods Hyperandrogenism Spironolactone Hyperinsulinemia Metformin Other oral diabetic medications

30 TREATMENT Hirsutism Infertility Chemical Mechanical
Depilatory (Hair removal methods) Chemical Mechanical Hormonal (Eflornithine 13.9%, Vaniqa®) Infertility Metformin Clomiphene Citrate

31 ORAL CONTRACEPTIVES Most efficient means of androgen suppression
(ovarian as well as adrenal) (Goodman, N et al., 2015 current best practices guide) First-line treatment for PCOS and menstrual irregularity In patients with cutaneous signs of androgen excess OCPs reduce hirsutism and acne

32 Obese adolescents 15-18 yrs Received Metformin for 6 months
Found to have increased ovulatory menstrual periods, reduction in testosterone and androstenedione and free testosterone. (Bridger T et al., 2006) Morin P et al

33 OCP vs. Metformin 60 PCOS patients (25 obese, 35 non-obese) enrolled in a prospective clinical study. Patients randomized to receive for 3 months OCP Diane35 (35 mcg ethinyl estradiol plus 2 mg cyproterone acetate), Metformin Combination of Diane35/metformin RESULTS: Testosterone levels decreased in all three groups Menstrual regularity was restored in all PCOS patients treated with OCP vs. 28% of those receiving metformin Metformin alone significantly decreased fasting insulin concentrations, and increased the insulin sensitivity in both obese and non-obese PCOS patients (Wu J et al., 2008) (Al Khalifah R et al., 2016)

34 ANTIANDROGENS Effective in improving facial hirsutism
Spironolactone: androgen receptor blockade Drospirenone: analogue of spironolactone Competitively inhibit androgen receptor binding Useful in the treatment of hirsutism Significant antiandrogenic activity Yasmin (OCP)Drospirenone combined with ethinyl estradiol Flutamide Finasteride

35 ANTIESTROGENS Clomiphene: selective estrogen receptor modulator
Widely used agent for ovulation induction in women with PCOS Increased FSH secretion from the pituitary removes the intraovarian block prohibiting the development of a dominant follicle Major side effect: multiple gestation

36 Other medications Glucocorticoids
In women with elevated adrenal androgens they suppress adrenal androgen secretion Used primarily in congenital adrenal hyperplasia (CAH) limited role in non-classic CAH GNRH-gonadotropin releasing hormone agonist In women with severe insulin resistance Improves severe forms of hirsutism “add-back” therapy with low-dose OCP is advised

37 BACK TO THE CASE An 18 y/o freshman presents for her annual visit but is also concerned that she may be depressed. She had menarche at age 14 and she has had menses every 2 months for the past 2 years, however has missed 4 months of her cycle most recently. She has a BMI of 29 and in the past year has experience increased facial hair growth. She has never had acne. She asks: “why do I have some much facial hair?”

38 CASE MANAGEMENT Abnormality In PCOS Metformin Spironolactone
(Anti-androgen) Oral Contraceptives Androgens Insulin resistance  no effect  / SHBG  Triglycerides HDL LH Normalize Ovulation or Irregular periods or Hirsutism  /sl Acne Obesity Insulin level

39 Non-classic Congenital Adrenal Hyperplasia (NCAH)

40 NCAH Objectives List the diagnostic criteria for NCAH
Understand the pathophysiology of NCAH Understand the approach to work-up of a patient with characteristics of NCAH Understand the different treatment modalities in the management of NCAH 40

41 CASE M.R. 19 year old female referred to Adolescent Medicine for menstrual irregularity Menarche 13 years old Initially menses would skip a month 4-5 months between menses now Menses last 5 days requiring 3-4 pads/day Endorses hair growth on upper lip, chin, and back 41

42 CASE M.R. Physical examination BMI 44
Genital exam: Tanner V, no evidence of clitoromegaly Skin: face notable for sideburns and hair above the upper lip and the chin diffuse hair on the chest, lower abdomen extending from umbilicus to the pubis, and legs and arms acne throughout the back and acanthosis nigricans of the neck Initial laboratory evaluation obtained and started on Provera 42

43

44 Classic Congenital Adrenal Hyperplasia
Autosomal recessive disorders resulting in impaired cortisol production due to an enzyme deficiency in the pathway of cortisol synthesis Elevation in ACTH and subsequent hormones before the deficient enzyme 90% cases due to mutations in CYP21A1 gene Encodes 21-hydroxylase enzyme

45

46 Classic Congenital Adrenal Hyperplasia
21-hydroxylase is an essential enzyme for the production of aldosterone and cortisol Impairment of 21-hydroxylase results in overproduction of hormonal products 17-OH progesterone Three pathways exist for the production of androgens in the absence of 21-hydroxylase

47 Steroid precursors prior to 21-hydroxylase shunted towards androgen production
Fig. 1. A, Normal fetal adrenal steroidogenesis. Because the fetal adrenal has low levels of 3β-HSD, most steroidogenesis is directed toward DHEA (and thence to DHEA-sulfate), but small amounts of steroid enter the pathways toward aldosterone and cortisol. The adrenal 21-hydroxylase, P450c21, is essential in both pathways. The adrenal can make small amounts of testosterone via 17β-HSD. B, In the absence of the 21-hydroxylase activity of P450c21, three pathways lead to androgens. First, the pathway from cholesterol to DHEA remains intact. Although much DHEA is inactivated to DHEA-sulfate, the increased production of DHEA will lead to some DHEA being converted to testosterone and dihydrotestosterone (DHT). Second, although minimal amounts of 17-OHP are converted to androstenedione in the normal adrenal, the huge amounts of 17-OHP produced in CAH permit some 17-OHP to be converted to androstenedione and then to testosterone. Third, the proposed backdoor pathway depends on the 5α and 3α reduction of 17-OHP to 17OH-allopregnanolone. This steroid is readily converted to androstanediol, which can then be oxidized to DHT by the reversible 3α-HSD enzyme. Although first discovered in marsupials, mass spectrometric examinations of human urinary steroid metabolites indicate this pathway may also occur in the human adrenal (78 ). Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab. 2010;95(9): doi: /jc J Clin Endocrinol Metab | This article is published under the terms of the Creative Commons Attribution- Non Commercial-No Derivatives License (CC-BY-NC-ND; 47

48 Classic Congenital Adrenal Hyperplasia
Presentation during neonatal period Genital ambiguity Classification Salt wasting Virilizing Salt wasting CAH presents early in infancy due to severe aldosterone deficiency with salt loss and adrenal crisis requiring immediate intervention Females with classic CAH with virilizing would have virlizing external genitalia Males with virlizing CAH often present with early virlization at ages 2-4 years of age

49 Non-Classic Congenital Adrenal Hyperplasia
Subclinical impairment of 21-hydroxylase resulting in decrease in enzymatic activity 20-50% residual 21-hydroxylase enzyme activity Androgen excess Mild reduction in cortisol production resulting in adrenal hyperplasia Mild reduced cortisol production stimulates ACTH secretion via reduction in negative feedback with increased ACTH levels causing adrenocortical growth and adrenal hyperplasia

50 As of 2010, 181 mutations have been reported in the CYP21A2 gene
CYP21A2 is the gene encodes for 21-hydroxylase. Deletions and/or large gene conversions of the entire gene and/or a limit number of point mutations comprise 95% of all mutations that cause 21-OH deficiency Panel A: shows CYP21 = the active 21-hydroxylase gene (formally called CYP21A2) and CYP21P= nonfunctional pseudogene (CYP21A1P). C4A & C4B encode the fourth component of serum complement, RP1 encodes a nuclear protein of unknown function, and RP2 is the corresponding truncated pseudogene. Panel B: 21-hydroxylase genes undergo an unequal crossover during meiosis and the resulting daughter chromosomes possess either 3 CYP21 alleles or one nonfunctional CYP21 gene as a result of a large deletion. Panel C: shows the positions of mutations normally found in CYP21P; any of these can be transferred to CYP21 in gene-conversion events. As of 2010, 181 mutations have been reported in the CYP21A2 gene

51 NCAH: Prevalence Prevalence
0.1–0.2% in the general Caucasian population 1–2% among Eastern European (Ashkenazi) Jews 1-2% among general Hispanic population One of the most common autosomal recessive diseases Frequency of heterozygote carriers 1:60 More common the CAH which is 1:15,00o births

52 NCAH: Presentation Presentation during childhood Premature pubarche
Clitoromegaly Advanced bone age Presentation during adolescence or adulthood Hirsutism Acne vulgaris Menstrual irregularity Asymptomatic with normal growth, puberty, and reproductive function More common the CAH which is 1:15,000 births Typically do not have virilized external genitalia but symptoms consistent with androgen excess

53 Female hirsutism and male pattern appearance
Texas Children’s

54 NCAH vs. PCOS PCOS physiology may develop due to chronic androgen excess and impact on H-P-A axis and ovaries ¼ of NCAH females have polycystic ovaries on ultrasound The clinical presentation of NCAH and PCOS can be identical Mandatory to exclude NCAH prior to the diagnosis of PCOS More common the CAH which is 1:15,00o births

55 NCAH: Genetic Testing Genotyping recommended for genetic counseling and confirmation of the diagnosis Risk of child with classic CAH More common the CAH which is 1:15,00o births

56 Risk to offspring Since most patients with NCAH carry one allele with a severe mutation for CYP21A2, for having offspring with classic CAH. A parent with NCAH would be predicted to have a 1 in 240 chance of having a child with classic CAH, (1/60 × ½) × (1 × ½). Since two thirds of NCAH patients are compound heterozygotes, the predicted incidence may be closer to 1 in 360 (1/60 × ½) × (2/3 × ½) One study in pregnant women with NCAH suggested risk of giving birth to child with classic CAH is more frequent (2.5%). Moran et al, JCEM 2006 Trapp et al, Steroids, 2012

57 NCAH: Testing NCAH usually not detected on newborn screen
Early morning ( ) 17-OH progesterone sample during the follicular phase in menstruating females Random sample if patient amenorrheic ACTH stimulation test Gold standard to diagnosis Genetic testing for CYP21A2 More common the CAH which is 1:15,00o births Not detected on newborn screen as NBS designed to detect higher levels of 17-OH progesterone as opposed to NCAH 17-OH levels In the US only one NCAH baby was identified out of 130,000 screened individuals 2-11% of NCAH missed using the early morning 17-OH progesterone approach -Can perform ACTH stim test even if normal basal 17-OH progesterone but have clinical suspicion

58 ACTH Stimulation Testing
Measurement of basal 17-OHP and at 60 minutes Consider measurement of basal and post-ACTH stimulation cortisol Early morning follicular phase 17-OHP levels of > 200 ng/dl should prompt further evaluation (will capture 90% of NCAH) More common the CAH which is 1:15,000 births Not detected on newborn screen as NBS designed to detect higher levels of 17-OH progesterone as opposed to NCAH 17-OH levels In the US only one NCAH baby was identified out of 130,000 screened individuals 2-11% of NCAH missed using the early morning 17-OH progesterone approach -Can perform ACTH stim test even if normal basal 17-OH progesterone but have clinical suspicion

59 Fig. 2. Diagnosis of CAH after infancy
Fig. 2. Diagnosis of CAH after infancy. Reference standards for hormonal diagnosis derived from Refs and Note that randomly measured 17-OHP levels can be normal in NCAH; hence, a screening 17-OHP level should be measured in the early morning (before 0800 h). Steroid measurements may differ with the assay employed. Classic CAH includes both salt-wasting and simple virilizing forms of 21-hydroxylase deficiency. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab. 2010;95(9): doi: /jc J Clin Endocrinol Metab | This article is published under the terms of the Creative Commons Attribution- Non Commercial-No Derivatives License (CC-BY-NC-ND; 59

60 CASE M.R. Elevated random 17-OH progesterone level: 229 ng/dl
Lab obtained at 12:12 pm DHEAS level: 57 mcg/dl Follow-up Responded to Provera challenge and started on OCPs for menstrual regulation Referred to Endocrinology for concern for non-classic congenital adrenal hyperplasia (NCAH) Endocrine initial appointment Repeat 17-OH progesterone 809 ng/dl (lab obtained at 9:06 am) Post-ACTH stimulation test: 17-OH progesterone 12,167 ng/dl Diagnosed with NCAH 17-OH progesterone range 60

61 NCAH Treatment Indications
Indicated only if patient is symptomatic and desires treatment Early onset puberty with rapid progression Adolescents and young adults with overt virilization Partial cortisol deficiency

62 NCAH Treatment Modalities
Glucocorticoids Consider if growth impacted Consider stress dosing during periods of illness, fever, or trauma Oral contraceptives Inhibition of androgen synthesis Impair ovarian production of androgen Increase of SHBG Spironolactone Cosmetic May have mild aldosterone insufficiency and can consider fludocortisone but dependent on benefits in relation to side effects such as hypertension and edema

63 Glucocorticoid Therapy
Pre-pubertal: hydrocortisone mg/m2/day in three divided doses Post-pubertal: dexamethasone mg/day Side effects of daily glucocorticoid therapy Adrenal insufficiency Low bone mineral density Cushing’s syndrome

64 NCAH: Complications Metabolic syndrome
Glucocorticoid therapy may result in increased risk of metabolic syndrome and cardiovascular morbidity Obesity and insulin resistance Cardiovascular complications Adrenal and testicular benign tumors Short stature Central precocious puberty Fertility less impaired in NCAH as appears to be dependent on severity of the mutation and not enough studies on male fertility with CAH

65 Comparing and Contrasting
PCOS & NCAH

66 PCOS vs. NCAH Clinical Presentation
Clinical Feature Prevalence Menstrual irregularity (eg, oligo- or amenorrhea, or irregular bleeding) 75% Hyperandrogenism (e.g, hirsutism, severe acne, and/or pattern alopecia) 60–80% Polycystic ovaries Obesity 35–80% History of infertility 60-75% Clinical Feature Prevalence Oligomenorrhea 54% Primary/Secondary amenorrhea 7%/6% No symptoms/FHx only 11% Acne 2% Hirsutism 78% Alopecia Premature pubarche 88% PCOS like-symptoms 63% Subfertility 12% Adrenal adenoma 3% Short stature 1%

67 PCOS vs. NCAH Work-up PCOS NCAH Labs Labs Early morning
Free and Total Testosterone DHEAS TFTs Prolactin 17-OH Progesterone LH: FSH >2:1 SHBG Androstenedione Insulin Labs Early morning 17-OH Progesterone Pre- and post- ACTH stimulation 17-OH Progesterone Pre- and post- ACTH stimulation cortisol Pre- and post-ACTH stimulation testosterone

68 PCOS vs. NCAH Treatment PCOS NCAH Menstrual irregularity
Oral contraceptives Hyperandrogenism Spironolactone Hyperinsulinism Metformin Hirsuitism Chemical/Mechanical removal Infertility Clomiphene Citrate Clomiphene citrate Growth Impairment Glucocorticoid Menstrual irregularity Oral contraceptives Hyperandrogenism Spironolactone Hyperinsulinism Metformin Hirsuitism Chemical/Mechanical removal Infertility Clomiphene Citrate

69 References Azziz, R et al.  Androgen Excess Society. (2006). Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome:an Androgen Excess Society guideline. The Journal of Clinical Endocrinology &Metabolism, (91)11, Barry, J., Kuczmierczyk, A & Hardiman, P. (2011). Anxiety and depression in polycystic ovary syndrome: a systematic review and meta-analysis. Human Reproduction, 26(9):2442–2451. Buggs, C. & Rosenfield, R. (2005). Polycystic ovary syndrome in adolescence. EndocrinolMetab Clin North Am, 34, 677–705. Chandra, A et al. (2013). Infertility and Impaired Fecundity in the United States, 1982–2010: Data From the National Survey of Family Growth.  Retrieved from Corona, M., McCarty, C., & Richardson, L. (2013). Screening adolescents for depression. Retrieved from Creatsas, G., Koliopoulos, C., & Mastorakos, G. (2000). Combined oral contraceptive treatment of adolescent girls with polycystic ovary syndrome. Lipid profile. Ann N Y Acad Sci, 900, Ehrmann, D. (2004).  Medical progress: polycystic ovary syndrome.  N Engl J Med, 352, 1223–1236. Goodman, N et al., (2015). AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY, AND ANDROGEN EXCESS AND PCOS SOCIETY DISEASE STATE CLINICAL REVIEW: GUIDE TO THE BEST PRACTICES IN THE EVALUATION AND TREATMENT OF POLYCYSTIC OVARY SYNDROME--PART 1. Endocr Pract, 21(11): Ghazeeri, G et al. (2013). Anxiety, Cognitive, and Depressive Assessment in Adolescents with Polycystic Ovarian Syndrome: A Pilot Study. Journal of Pediatric and Adolescent Gynecology, 26(5): Khalifah, R et al. (2016). Metformin or Oral Contraceptives for Adolescents With Polycystic Ovarian Syndrome: A Meta-analysis. Pediatrics, 137(5). Kroenke, K., & Spitzer, R. (2002). The PHQ-9: a new depression and diagnostic severity measure. Psychiatric Annals,32, Laggari, V et al., (2009). Anxiety and depression in adolescents with polycystic ovary syndrome and Mayer-Rokitansky-Küster-Hauser syndrome. J Psychosom Obstet Gynaecol, 30(2):83-8. Michelmore, K., Balen, A., & Dunger, D. (2001). Polycystic ovaries and eating disorders: Are they related? Hum Reprod, 16(4):765-9. National Institutes of Health. (2012). Evidence-based Methodology Workshop on Polycystic Ovary Syndrome.  Executive Summary.  Retrieved from Rosenfield, R. (2012). Definition, pathogenesis, and etiology of polycystic ovary syndrome in adolescents. Retrieved from: Last updated Dec 13, 2012 Sirmans, S., & Pate, K. (2014). Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clinical Epidemiology, 6, 1–13. Trent, M., Rich, M., Austin, S., & Gordon, C. (2003). Fertility Concerns and Sexual Behavior in Adolescent Girls with Polycystic Ovary Syndrome: Implications for Quality of Life. Journal of Pediatric and Adolescent Gynecology, 16(1), 33–37. Trent, M., Rich, M., Austin, S.,& Gordon, C. (2001). Polycystic ovary syndrome in adolescent girls: Fertility concerns and sexual behavior.   Journal of Pediatric and Adolescent Gynecology, 14(31),144. 

70 References Falhammar, H., & Nordenström, A. (2015). Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Clinical presentation, diagnosis, treatment, and outcome. Endocrine, 50(1), Merke, D. P., & Poppas, D. P. (2013). Management of adolescents with congenital adrenal hyperplasia. Lancet Diagetes Endocrinology, 1, Trapp, C. M., & Oberfield, S. E. (2012). Recommendations for treatment of nonclassic congenital adrenal hyperplasia (NCAH): An update. Steroids, 77(4), White, P. C. (2000). Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. Endocrine Reviews, 21(3), Pall , M., Azziz, R., Beires, J., & Pignatelli ,D. (2010). The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Fertil Steril. 94(2), 684-9

71 Thank you! Dr. David McBride Dr. Kim Shimy

72 Questions? Contact information Serwa Gyamfi, MD Sharyn Malcolm, MD, MPH


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