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

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

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

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