Dr Georgina HawkinsGeneral Obstetrician and Gynaecologist

Fertility Associates

Christchurch

8:20 - 8:40 When Puberty is PCO

When Puberty is PCOS

Dr Georgina HawkinsRANZCOG advanced trainee

Fertility Associates Christchurch

None to declare

No sponsorship to attend conference

Conflict of Interest

Case

PCOS clinical features and pathophysiology

Diagnostic Criteria - adults

Diagnostic Criteria – adolescents

When to investigate

Basic work up

Basic management and follow up

Take home messages

Overview

Alice, 35yo G0P0

Presents to fertility clinic to discuss ‘social egg freezing’

Dx PCOS and started on COCP age 15

Concerned as she was told she would likely be ‘infertile’

Recent new relationship of 6/12 so not ready to start family yet

Case

HCG NegDay 3 FSH 5.9IU/L, LH 5.2IU/LDay 3 Oestradiol 106pmol/LDay 21 progesterone 39nmol/LAMH 16pmol/L (45th centile for age)TSH 1.9 normalPRL 225 normalBooking bloods unremarkableSmear and Swabs NAD

Alice: Investigations

Affects 8-13% of reproductive aged women

Key features include:

Clinical or biochemical hyperandrogenism

Anovulation

Polycystic ovarian morphology

ReproductiveMenstrual irregularityHirsutism/AcneInfertilityPregnancy complications

MetabolicInsulin ResistanceAcanthosis nigricansMetabolic syndrome, ObesityPrediabetes, DiabetesCardiovascular risk factors

PsychologicalAnxietyDepressionLow self imageDisordered eating

PCOS Overview

Stein and Leventhal 1935

National Institutes of Health (NIH) 1990

Rotterdam Criteria 2003

Androgen Excess and PCOS society 2006

CRE-PCOS due 2018

Diagnostic criteria

Women present with a diverse range of clinical features that vary across the lifespan and between ethnicities

Multiple classification systems have been developed over the years

Defining individual components within the diagnostic criteria is challenging

Changes in the understanding of the pathophysiology

Why is PCOS so hard to define?

PCOS Pathophysiology

LH stimulates androgen production in ovarian theca cells

Androgen usually aromatised to estrogen in granulosa cell

High local androgens are converted to potent 5α-reduced androgens which prevent follicular development

New follicle growth continues but arrests before maturation is achieved – resulting in multiple small follicles surrounded by hyperplastic theca cells: PCO

PCOS pathophysiology

2 out of 3 of the following

1. Oligo/anovulation

2. Clinical or biochemical evidence of hyperandrogenism

3. PCOM on USS

And the exclusion of other causes of androgen excess (thyroid disease, non-classic congenital adrenal hyperplasia NCCAH, hyperprolactinaemiaand androgen-secreting tumours)

Rotterdam criteria 2003Endorsed by CRE-PCOS

Adolescents are not adults!

PCOS

Anovulation

Hyperandrogenism

Hirsutism

Acne

Increased serum androgens

PCOM on USS

Syndrome of insulin resistance

Puberty

Anovulatory cycles common

Changes in body hair type and distribution

Acne

Rise in testosterone levels in anovulatory cycles

PCOM on USS

Transient Insulin resistance not uncommon

Adolescent diagnosis is problematic

Comparison of PCOS symptoms with normal changes at puberty:

Menstrual irregularity

Hirsutism

Acne

Acanthosis nigricans

Obesity

Is it puberty or PCOS?

An otherwise unexplained combination of both:

1. Abnormal uterine bleeding patterna. Abnormal for age (see table next slide)b. Persistent symptoms for at least 1- 2 years

2. Evidence of hyperandrogenisma. Increased testosterone above adult norms in a reliable reference lab b. Moderate to severe hirsutism (clinical evidence of hyperandrogenaemia)c. Moderate to severe inflammatory acne vulgaris (an indication to test for hyperandrogenaemia)

Based on Witchel S, Oberfield S, Rosenfield R, Codner E, Bonny A, Ibáñez L, et al. The Diagnosis of Polycystic Ovarian Syndrome during Adolescence Horm Res Pediatr. 2015;83 (6):376–389.From Pediatrics, Vol 136, pages 1154-65

Diagnostic criteria for PCOS in adolescencePaediatric Endocrine Society 2015

Primary Amenorrhoea Lack of menarche by age 15 or by 3 years after breast development

Secondary Amenorrhoea >3/12 no period after previous menstruating

Oligomenorrhoea Year post menarche

1 Cycle length >90 days

2 Cycle length > 60 days

3-5 Cycle length >45 days

6+ Cycle length >38 days

Excessive uterine bleeding

cycles <19 days or longer then 7 days

Adolescent cycles Usually 21-45 days

Differentiating menstrual disorder from normal adolescent cycles

Hirsutism Abnormal amount of sexual hair that appears in a male pattern(vs hypertricosis - generalised increase in vellus, non sexual hair)Use modified Ferrimen-Gallwey score to assess:>8 = indication for investigation with serum androgens>15 = moderate hirsutism (sufficient for a diagnosis of hyperandrogenism)

Acne Moderate or severe inflammatory acne (>10 lesions in either face,chest, back) that has not responded to topical treatment issupportive of hyperandrogenism

Female patternhair loss

Virilisation Rare; suspect if: voice deepening, clitoromegaly, severe rapidlyprogressive hirsutism, male pattern hair loss

Hyperandrogenism: clinical thresholds for diagnosis

50% of hyperandrogenic femalesdo not have hirsuitism or acne

Ferriman-Galwey

Standard Investigations:

1. Total testosterone - normal/increased◦ Normal range = 1.4-2.1 nmol/L◦ PCOS - most will have values <5.2 nmol/L◦ >6.9 nmol/L warrants referral to endocrine to exclude virilising

tumour

2. Calculated Free Testosterone or Free Androgen index -increased

3. SHBG - reduced

Hyperandrogenism: biochemical features

Useful but not part of diagnostic criteria:

AMH - elevations >2 fold are highly specific for PCOS LH: FSH ratio >2-3 is highly suggestive of PCOS

Not routinely required:

DHEA-S - a marker of adrenal androgen synthesis and is moderately elevated in half of PCOS but significantly elevated levels indicate a potential adrenal source (measure if concern for severe or rapidly progressive hyperandrogenism or virilisation)

Other androgens - androstenidione and DHEA require conversion to testosterone to exert androgenic effects and so measurement adds little value

Additional laboratory investigations

TSH

PRL

Day 3 FSH to exclude POF

If raised testosterone → early morning (8am) 17-OHP in follicular phase to rule out non classic congenital adrenal hyperplasia due to 21 hydroxylase deficiency (NCCAH)◦ <6 nmol/L excludes the condition

◦ >30 nmol/L is diagnostic

◦ If unsure refer to endocrine for ACTH stimulation test

Serum cortisol if central obesity ◦ <276 nmol/L reassuring against Cushings

IGF-1 (growth hormone excess is usually identified by characteristic clinical fx but can present similarly to PCOS)

Additional Tests to exclude conditions that mimic PCOSPCOS is a diagnosis

of exclusion

25-50% of normal adolescents meet adult USS criteria for PCOM (AFC ≥12 or ovarian volume >10 ml

Adolescents often have multi-follicular, slightly enlarged ovaries

New high resolution vaginal USS show that small antral follicle counts of up to 24 are normal

The quandary of polycystic ovary morphology in adolescence

USS is not recommended in assessment of PCOS in adolescents and is notrequired for diagnosis

Treatment is primarily symptomatic, directed at:

Abnormal uterine bleeding: COCP (any)

Cutaneous hyperandrogenism: COCP; add anti-androgens (spironolactone 100-200mg daily in divided doses) if no improvement after 6/12 on COCP

Obesity and insulin resistance: metformin

Comorbidities of metabolic syndrome: weight management; lifestyle interventions; exercise

Management

Reduce risk for T2DM, metabolic syndrome and CVD◦ Monitor HbA1c, fasting glucose or OGTT (1-2 yearly)◦ Monitor lipid profile (1-2 yearly)◦ Monitor BP◦ Weight and waist circumference (yearly)◦ Assess risk factors for CVD – smoking, inactivity

Reduce risk for endometrial hyperplasia and cancer (through chronic unopposed estrogen)◦ Avoid prolonged periods of ameno/oliomenorrhoea (schedule withdrawal bleeding with

COCP or cyclic progestin)◦ Low threshold for investigation for abnormal menstrual bleeding with TVUS and endometrial

bx

Long-term goals

1. Menstrual abnormalities in adolescents are common and should be assessed according to age and stage of puberty

2. Consider PCOS in presentations of obesity, hirsuitism, severe acne, acanthosis nigricans and/or depression (menstrual abnormalities may not be the chief complaint)

3. Caution in labelling hyperandrogenic adolescents as PCOS if the menstrual abnormality has not persisted for >2 yrs

4. In the interim, consider these patients as ‘at risk for PCOS’ and review periodically

5. However, if symptoms are sufficiently severe to require treatment, do not delay initiation of diagnostic work up

6. USS is not recommended or required in the assessment and diagnosis of PCOS in adolescents

Take home messages

Alice Menarche age 14, normal BMI Had periods every 2-3 months Mild-Moderate acne, no hirsutism Transabdominal scan 1996 described PCO Off COCP now having regular cycles, no recurrence of acne normal AMH, androgen profile normal Had 2 cycles of COS, total 12 eggs frozen. Conceived spontaneously with

new partner 6 months later!

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