PCOS – Where does it come from, where does it go to?

Roy Homburg

2

Polycystic ovary syndrome (PCOS)

Criteria*:

• oligo- or anovulation

• clinical and/or biochemical signs of hyperandrogenism

• polycystic ovaries on ultrasound

*2003 Rotterdam PCOS consensus

Barker hypothesis‘developmental origin of adult disease’

‘The womb may be more important than the home’

PCOS - Candidate Genes

PCOS is strongly familial

Genetically defined basis not found – almost all initial candidates failed to maintain linkage with PCOS phenotype

? inheritance is modified by environmental factors

? Re-programming of genes in utero.

Excess androgens in utero- defeminization of sexual functionPrenatal maternal testosterone levels –

dose-related link with gender role behaviour in pre-school girls (Hines et al, 2002)

Girls exposed to high levels of T pre-natally (CAH) show distinct masculine-type behavioral traits (Berenbaum & Hines, 1992)

Traits also correlate with T levels in amniotic fluid (Grimshaw et al, 1995)

Discrete Prenatal Androgen Excess During Gestation

(10-15 mg testosterone propionate injected s.c. daily into pregnant mothers)

Early Treated (15-35 days)Early Treated (15-35 days)

Days of GestationDays of Gestation

165165 110 110555500

n = 5 - 11 n = 5 - 11

n = 5 - 9n = 5 - 9

Late Treated (15-25 days)Late Treated (15-25 days)

Starting on Day 40-44

Starting on Day 40-44

Starting on Day or Day 100 115

Starting on Day or Day 100 115

conceptionconception parturitionparturition

1ST trimester1ST trimester 2ND trimester2ND trimester 3RD trimester3RD trimester

0

0.1

0.2

0.3

0.4

0.5

40 60 80 100 120 140

Gestation days

0

4

8

12

16

20

24

28

32

36

ng

/ml

40 60 80 100 120 140

Gestation days

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30

Postnatal days

Serum testosterone levels

TP injected females (n=9)

Oil injected controls (n=5)

* P < 0.001 vs controls

TP injected

Oil injected

Backtransformed means 95% CI

(a) Mothers

(b) Fetuses (c) Infants

TP injected mothers

Oil injected mothers

*

*

*

Ovulatory menstrual cycles in control and prenatally androgenized females over a 6-month period

7 *†

p < 0.02 vs. controls

p < 0.03 vs. controls

Control females( n = 6)

Early PA females ( n = 6 )

Late PA females( n = 5 )

0

1

2

3

4

5

6

*†

Number of cycles per six month period

Late-treated(n = 3)

0

5

10

15

20

25

30

35

ng/ml

Controlfemales(n = 24)

Early-treated(n = 10)

prenatally androgenizedfemales

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

ng/ml

Controlfemales(n = 5)

Early-treated(n = 4)

Late-treated(n = 5)

prenatally androgenizedfemales

Late-treated(n = 3)

0

5

10

15

20

25

30

35

ng/ml

Controlfemales(n = 24)

Early-treated(n = 10)

prenatally androgenizedfemales

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

ng/ml

Controlfemales(n = 5)

Early-treated(n = 4)

Late-treated(n = 5)

prenatally androgenizedfemales

Serum Levels of (a) immuno-LH in 13-14 year old Females during the Follicular Phase and (b) bioactive LH in 18-20 year old Females

***

*** p < 0.001 vs controls

*

* p < 0.03 vs controls

(a) (b)

In the beginning…. A excess in utero Programming of

PCOS

Insulin + LH Pre/small antral Thecal follicle number enzymesserine phosphorylation

Androgen excess

Hypothesis for Prenatal Androgen Programming of Females for PCOS

Hypothesis for Prenatal Androgen Programming of Females for PCOS

Developmental origin of PCOS

prenatal/prepubertalexposure to androgen

hCG/LH

hyperandrogenaemia

central adiposity

abnormal LH secretion

insulinresistance

2

1

1 genes regulating•folliculogenesis•steroidogenesis (CYP11a )

2 genes regulating•insulin secretion ( INS-VNTR)•insulin action•adipocyte differentiation

anovulation

Developmental origin of PCOS

prenatal/prepubertalexposure to androgen

hCG/LH

hyperandrogenaemia

central adiposity

abnormal LH secretion

insulinresistance

2

1

1 genes regulating•folliculogenesis•steroidogenesis (CYP11a )

2 genes regulating•insulin secretion ( INS-VNTR)•insulin action•adipocyte differentiation

anovulation

Abbott et al (2002) J Endocr. 174:1-5

16

Androgens in girls with PCOS mothers

Does prenatal exposure to androgens cause PCOS?

Origin of androgens in PCOS women:

• Maternal origin placental passage during gestation

• Fetal origin is the fetus making the androgens?

The androgen circle of PCOS

XS androgens

Exposure In utero

Multiple smallfollicles

InsulinLH

AMH

AnovulationHirsutismAcne

PCOSphenotype

Homburg R, Hum Reprod, 2009

One in every five women

has polycysticovaries.

Polycystic Ovary Syndrome(PCOS)About 20% of the female population have polycystic ovaries.

5-10% of the female population suffer from symptoms.

Manifestations of PCOSMenstrual

disturbance Hirsutism

Acne Infertility

Obesity

High LH

High Testosterone

Hyperinsulinemia

Ultrasound appearance

Manifestations of PCOSMenstrual

disturbance (66%)Hirsutism (66%)

Acne (35%)Infertility (75%)

Obesity (38%)

LH up (40%)T up (30%)

Insulin up - in obese 80%

- in slim 30-40%

RANGE OF PCOS

I_______________________________I

NORMAL OVULATORYCYCLES, MILD HIRSUTISM

AMENORRHEAHIRSUTISM/ACNEINFERTILITYOBESITY

* The fundamental disturbance of PCOS involves a primary lesionin the ovary.

* The expression of the lesion is determined in part by extra-ovarian factors.

ultra-sound

hormones

symptoms OBESITY

INSULIN

after Dewailly, 2003

ultra-sound

hormones

symptoms

OBESITY

INSULIN

WEIGHTLOSS

after Dewailly, 2003

Main disturbances in PCOS Abnormal steroidogenesisIncreased ovarian production of:

Androgens

Progesterone Estradiol

Androstendione17,20 lyase

17OHaseP450c17

INSULIN

rLH + LH

free IGF-1

serine phosphorylation

E2

TGFa / EGF

/ /

__+

_ Follistatin

cholesterol

P450scc

pregnenelone

FSH +

http://www.posterrevolution.com/poster.cfm/vw-splitty-art-print-poster-24x36

PCOS morphologyx6 the density of pre-antral follicles compared with normal ovary .

(Webber et al, 2003)

Large cohort of small follicles arrest in development but capable of responding to exogenous FSH.

Human Follicle Growth

(Gou

geon

, E

ndoc

r R

ev 1

996)

Primary follicle1 layer cuboidal GCs )46 µm, 570(

Secondary follicle 2 layers of GCs )77 µm, 480(

Pre-antral follicleclass 1 )theca cells & arterioles( )120 µm, 350(

Early antral follicleclass 2 )180-250 µm, 170(

Small antral follicleclass 4 )2 mm, 25(

Primordial follicle1 layer flat granulosa cells )36µm, 570(

ANDROGENS ++

Accelerated follicular development 2-5mm

Primordial

Pre-antral

Early antral

Arrest of development

XS early antral follicles (PCO)

Insulin +LH +

AnovulationA excess LH +insulin

Multiple small follicles

AMH E2

FSH action

Anovulation progesterone

Insulin

LH

P450c17 Androgen excess

Free Testosterone +

Dihydrotestosterone

5alpha-reductase

Hirsutism,Acne

SHBG

Dermatological symptoms

PCOS - Late sequelaeHyperinsulinemia / hyperandrogenism / obesity

• Diabetes mellitus x7

• Hypertension x4

• Low HDL/high LDL

*All are risk factors for cardiovascular disease and CVA

Main disturbances in PCOS Insulin resistance

80% of obese PCOS

30-40% of lean PCO

Genetic post-receptor defect unique to PCO

• Exaggerated by obesity

Metabolic syndromeAbdominal obesity (waist >88 cm)Triglycerides (>150 mg/dl)HDL cholesterol (<50 mg/dl)BP >130/>85Glucose (fasting >110, 2hr >140 mg/dl)

Any 3 out of 5

Sleep Disorders in PCOSPCOS n=53, controls n=452

0102030405060708090

SleepApnea

DaytimeSleepiness

PCOS N=53Controls N

=452

Risk of Sleep Apnea in PCOS

Odds Ratio 29

(95% CI 5-294)

Adjusted for differences in

BMI

Vgontzas et al, JCEM, 2001

Copyright ©2001 The Endocrine Society

Fogel, R. B. et al. J Clin Endocrinol Metab 2001;86:1175-1180

Elevated Testosterone in PCO Associated with Sleep Apnea

The androgen circle of PCOS

XS androgens

Exposure In utero

Multiple smallfollicles

InsulinLH

AMH

AnovulationHirsutismAcne

PCOSphenotype

Homburg R, Hum Reprod, 2009